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PURPOSE: MDM2, a negative regulator of the TP53 tumor suppressor, is oncogenic when amplified. MDM2 amplification (MDM2amp) is mutually exclusive with TP53 mutation and is seen in 6% of patients with lung adenocarcinoma (LUAD), with significant enrichment in subsets with receptor tyrosine kinase (RTK) driver alterations. Recent studies have shown synergistic activity of MDM2 and MEK inhibition in patient-derived LUAD models with MDM2amp and RTK driver alterations. However, the combination of MDM2 and RTK inhibitors in LUAD has not been studied. METHODS: We evaluated the combination of MDM2 and RTK inhibition in patient-derived models of LUAD. RESULTS: In a RET-fusion LUAD patient-derived model with MDM2amp, MDM2 inhibition with either milademetan or AMG232 combined with selpercatinib resulted in long-term in vivo tumor control markedly superior to either agent alone. Similarly, in an EGFR-mutated model with MDM2amp, combining either milademetan or AMG232 with osimertinib resulted in long-term in vivo tumor control, which was strikingly superior to either agent alone. CONCLUSION: These preclinical in vivo data provide a rationale for further clinical development of this combinatorial targeted therapy approach. [ABSTRACT FROM AUTHOR]

Background: The advent of biologics and janus kinase inhibitors has revolutionized treatment of atopic dermatitis (AD). Objective: To investigate preferences of patients with AD for attributes of currently approved systemic treatments and assess influencing factors. Methods: An online discrete choice experiment was conducted in patients with AD throughout Germany to analyze preferences for outcome (probability of (almost) clear skin at week 16, probability of significant itch improvement, time to onset of itch relief and type of side effects) and process attributes (application method and frequency of laboratory tests). Results: Participants (n=182, 75.3% female) considered side effects (Relative Importance Score (RIS): 31.2), (almost) clear skin (RIS: 24.2) and probability of itch improvement (RIS: 16.0) most important. Application method (RIS: 14.4), time to onset of itch relief (RIS: 7.4) and frequency of laboratory tests (RIS: 6.8) were less relevant. Preferences were significantly influenced by sex, age, psychiatric comorbidity, current therapy and health-related quality of life according to multivariate regression analysis. Conclusions: Participants attached great importance to safety and symptom control. However, preferences were also dependent on individual characteristics, underscoring the importance of personal counseling. Conjoined with medical considerations, patients’ preferences have fundamental impact on shared decisions for treatment of AD. [ABSTRACT FROM AUTHOR]

Background: Janus kinase 1 inhibitor upadacitinib is therapeutically effective for atopic dermatitis (AD). However, predictive factors for high responders to upadacitinib have not been established in real-world clinical practice. Objectives: To identify predictive factors for responders to upadacitinib 15mg or 30mg, defined as achievers of investigator’s global assessment (IGA) 0/1 with ≥ 2-point improvement from basal IGA. Methods: A retrospective study was conducted from August 2021 to July 2023 on 159 AD patients treated with upadacitinib 15mg and 52 patients with 30mg. Patients in each group were categorized into responders (achievers of IGA 0/1 at week 12) and non-responders (non-achievers). We compared baseline values of clinical and laboratory parameters between responders and non-responders. Logistic regression analysis was used to detect variables predicting responders. Receiver-operating characteristic curves were used for evaluating prediction capabilities of the variables. Results: In logistic regression analysis, responders to 15mg upadacitinib were associated with lower total EASI and higher age whereas responders to 30mg were associated with lower LDH and lower IgE. Conclusions: Lower total EASI and higher age may predict responders to upadacitinib 15mg while lower IgE and lower LDH may predict responders to 30mg. [ABSTRACT FROM AUTHOR]

Background: Previous clinical trials presented efficacy and safety of Janus kinase 1 inhibitor upadacitinib through 52weeks for moderate-to-severe atopic dermatitis (AD). Objectives: To assess the effectiveness and safety of upadacitinib through 48weeks in real-world clinical practice for Japanese AD patients (aged ≥12years). Methods: This retrospective study included 287 patients with moderate-to severe AD treated with 15mg (n=216) or 30mg (n=71) of upadacitinib daily. Effectiveness was assessed using eczema area severity index (EASI) scores, atopic dermatitis control tool (ADCT), peak pruritus-numerical rating scale (PP-NRS), and investigator’s global assessment (IGA). Safety was evaluated through the incidence of treatment-emergent adverse events. Results: From baseline, EASI, ADCT, PP-NRS, and IGA rapidly reduced at week 4, and the reduction was maintained until week 48 of treatment with upadacitinib at both doses. Achievement rates of EASI 75, EASI 90, and EASI 100 at week 48 were 63.5, 30.2, and 7.9 in 15mg group, and 77.4, 54.8, and 3.2% in 30mg group, respectively. Acne and herpes zoster were frequent, but no serious adverse events occurred. Conclusions: Upadacitinib was therapeutically effective and tolerable for moderate-to-severe AD through 48weeks in real-world clinical practice. [ABSTRACT FROM AUTHOR]

Background: Though Janus kinase inhibitors such as upadacitinib rapidly relieve itch in atopic dermatitis (AD) patients, how early itch relief impacts later skin clearance is not examined. Objectives: This study aims to determine if early itch relief by upadacitinib could predict complete skin clearance in later phases. Methods: This retrospective study involved 105 patients with moderate-to-severe AD treated with upadacitinib 15mg/day. Eczema area and severity index (EASI), atopic dermatitis control tool, and achievement rate of EASI 100 were evaluated at weeks 4, 12, and 24. The threshold of early peak pruritus-numerical rating scale (PP-NRS) predicting later skin clearance was assessed by area under the receiver-operating characteristic curve, and predictors for EASI 100 achievement were determined by logistic regression analysis. Results: The rate of achieving EASI 100 at week 24 was extremely higher in patients who achieved week 2 PP-NRS ≤ 1 (42.9%) than in non-achievers (1.4%). The logistic regression analysis showed that the achievement of week 2 PP-NRS ≤ 1 and low body mass index were associated with achievement of EASI 100 at weeks 12 and 24. Conclusions: The achievement of week 2 PP-NRS ≤ 1 may predict later skin clearance in upadacitinib treatment. [ABSTRACT FROM AUTHOR]

Metastatic renal cell carcinoma (mRCC) carrying sarcomatoid features (sRCC) has aggressive biology and poor prognosis. First‐line immunotherapy (IO)‐based combinations have improved the outcome of clear cell RCC patients, including that of sRCC. Real‐world data confirming the adequate first‐line management of sRCC is largely lacking. We investigated the clinical features and the outcome of sRCC patients treated with IO‐based combinations within the ARON‐1 study population (NCT05287464). The primary objective was to define the incidence and baseline clinical characteristics of sRCC compared with non‐sRCC patients. The secondary objective was to describe the outcome of sRCC patients based on type of first‐line treatment (IO + IO vs. IO + tyrosin kinase inhibitor [TKI]). We identified 1362 mRCC patients with IMDC intermediate or poor risk, 226 sRCC and 1136 non‐sRCC. These two subgroups did not differ in terms of baseline characteristics. The median overall survival (OS) was 26.8 months (95%CI 21.6–44.2) in sRCC and 35.3 months (95%CI 30.2–40.4) in non‐sRCC patients (p =.013). The median progression‐free survival (PFS) was longer in non‐sRCC patients compared to sRCC (14.5 vs. 12.3 months, p =.064). In patients treated with first‐line IO + TKI the median OS was 34.4 months compared to 26.4 months of those who received IO + IO (p =.729). The median PFS was 12.4 months with IO + TKI and 12.3 months with IO + IO (p =.606). In conclusion, we confirm that sRCC are aggressive tumors with poor prognosis. IO‐based combinations improve survival outcomes of sRCC patients, regardless from the type of strategy (IO + IO versus IO + TKI) adopted. [ABSTRACT FROM AUTHOR]

AURKA is a threonine or serine kinase that needs to be activated by TPX2, Bora and other factors. AURKA is located on chromosome 20 and is amplified or overexpressed in many human cancers, such as breast cancer. AURKA regulates some basic cellular processes, and this regulation is realized via the phosphorylation of downstream substrates. AURKA can function in either the cytoplasm or the nucleus. It can promote the transcription and expression of oncogenes together with other transcription factors in the nucleus, including FoxM1, C-Myc, and NF-κB. In addition, it also sustains carcinogenic signaling, such as N-Myc and Wnt signaling. This article will focus on the role of AURKA in the nucleus and its carcinogenic characteristics that are independent of its kinase activity to provide a theoretical explanation for mechanisms of resistance to kinase inhibitors and a reference for future research on targeted inhibitors. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction Aim Materials/Methods Results Conclusion Alopecia areata is a common autoimmune disease which results in reversible hair loss. Janus kinase inhibitors are prescribed for severe alopecia areata with encouraging results. There are no studies comparing the efficacy and safety of Janus kinase inhibitors to traditional treatment options, such as topical immunomodulators and traditional immunosuppressants.To retrospectively compare the efficacy and safety of baricitinib, an approved Janus kinase inhibitor, to other treatments for severe AA during a 6‐month treatment period.We included patients with newly presenting, relapsing or treatment‐resistant alopecia areata with Severity of Alopecia Tool (SALT) score ≥ 50, for the period between July 2021 and July 2023. Medical histories were reviewed and possible side effects were recorded. Primary endpoints were SALT ≤ 20 and SALT ≤ 10 after 6 months of treatment.Seventy‐five patients (53 females) were divided into three groups: topical immunomodulators (51 patients); baricitinib (19 patients); and a group receiving pulsed intramuscular corticosteroids or traditional immunosuppressants (11 patients). Twenty‐one patients received more than one treatment options within 2 years. After 6 months, the baricitinib group showed superior efficacy with 32% and 26% of patients achieving SALT ≤ 20 and SALT ≤ 10, compared to 12% and 9% in both other groups. Baricitinib demonstrated better secondary outcomes (50% and 90% reduction from initial SALT scores). All treatments exhibited mild‐to‐moderate and expected side effects. Weight gain, which had not been reported in clinical trials for alopecia areata, was observed in three baricitinib‐treated patients.Baricitinib was superior to traditional treatments for severe alopecia areata after 6 months. Weight gain concerned 16% of patients receiving baricitinib. [ABSTRACT FROM AUTHOR]

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are the most applied targeted therapy for EGFR-mutant lung adenocarcinoma (LUAD). The third-generation EGFR-TKI, osimertinib, is widely used throughout lung cancer treatment, with single or combination modes. One of the main barriers in osimertinib treatment is the acquired resistance and mechanisms are not fully understood. Gene expression other than genetic mutations might predict drug response and mediate resistance occurrence. We analyzed six datasets of osimertinib-resistant LUAD cells from the Gene Expression Omnibus (GEO) database and identified two hub genes, named MRAS and HEG1. We found that the expression mode of MRAS/HEG1 in LUAD was osimertinib-dependent and contributed to drug resistance. We also explored potential mechanisms of hub genes related osimertinib resistance and emphasized the M2 infiltration involved. Moreover, potential therapeutic agents conquering MRAS/HEG1-related resistance were also identified. In conclusion, MRAS and HEG1 might be responsible for osimertinib resistance and could be promising prognostic biomarkers for osimertinib response in LUAD, which might provide insights into therapeutic strategies. [ABSTRACT FROM AUTHOR]

Phosphosignaling networks control cellular processes. We built kinase-mediated regulatory networks elicited by thrombin stimulation of brain endothelial cells using two computational strategies: Temporal Pathway Synthesizer (TPS), which uses phosphoproteomics data as input, and Temporally REsolved KInase Network Generation (TREKING), which uses kinase inhibitor screens. TPS and TREKING predicted overlapping barrier-regulatory kinases connected with unique network topology. Each strategy effectively describes regulatory signaling networks and is broadly applicable across biological systems. [ABSTRACT FROM AUTHOR]

Janus kinase inhibitors (JAKis) represent a fundamental therapeutic tool for the treatment of patients with immune-mediated inflammatory diseases. Although JAKis are often considered a homogeneous class of drugs whose members are thought to be largely interchangeable, there are significant differences in their efficacy and safety profiles. This narrative review analyzes the pharmacokinetic and pharmacodynamic differences among JAKIs, highlighting their clinical relevance based on the most recent available evidence. The article aims to provide rheumatologists, gastroenterologists and dermatologists with practical guidance for choosing the most appropriate JAKi for each patient, given the lack of evidence-based recommendations on this topic, to improve clinical outcomes. Due to its preferential action on JAK1, intestinal metabolization and proven absence of impact on male fertility, filgotinib may be characterized by an improved benefit/risk ratio compared with other less selective JAKis. [ABSTRACT FROM AUTHOR]

Head and neck squamous cell carcinoma (HNSCC) is highly enriched with tumor-infiltrating myeloid cells, including tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). However, effective therapeutic agents targeting tumor-associated myeloid cells in HNSCC are currently lacking. Here, we employed a unique co-culture system to investigate how HNSCC cells affect tumor-associated myeloid cells. We found that the presence of cancer cells significantly enhances myeloid cell proliferation and promotes TAM differentiation. To identify potential therapeutic agents, we screened a custom library of 70 kinase inhibitors to assess their effects on distinct subsets of tumor-associated myeloid cells. We discovered specific inhibitors that differentially suppressed the populations of TAMs, monocytic MDSCs (M-MDSCs), or polymorphonuclear MDSCs (PMN-MDSCs), suggesting that inhibiting different targets could reduce distinct subsets of tumor-associated myeloid cells. Conversely, some inhibitors were found to increase the population of CD11b+Ly6G−Ly6C− myeloid cells. Among the promising inhibitors tested, vatalanib, a VEGF-R inhibitor, demonstrated significant in vivo efficacy at inhibiting tumor growth and reducing tumor-associated myeloid cells, thereby underscoring its potential as a therapeutic agent. Our findings highlight specific kinase inhibitors with differential modulatory effects on HNSCC-associated myeloid subsets and caution the application of some as anti-cancer drugs. This experimental system may provide a robust platform for identifying new agents targeting tumor-associated myeloid cells in HNSCC and beyond, and for elucidating mechanistic insights into tumor-myeloid cell interaction. [ABSTRACT FROM AUTHOR]

Inserting Isatin (1H indole 2,3‐dione) stands out as an exceptionally captivating element in the realm of drug design and development. Hence, there has been a notable focus in numerous anticancer studies on investigating the potential of various derivatives of Isatin (1H indole 2,3‐dione), including imines, hydrazones, thiosemicarbazones, and other compounds. Therefore, to develop new compounds with anticipated high activity, a novel series of 40 Isatin derivatives have undergone 3D‐QSAR studies as potent anticancer agents against the leukemia cell line (K562). This approach has been pursued due to the significant importance placed on exploring the potential of these derivatives. Through the analysis of graphical contour maps, the generated models yielded favorable statistical outcomes and provided valuable insights into the structural elements that exert a significant influence on the activity. Furthermore, both CoMFA and CoMSIA models have shown suitable reliabilities (q2 = 0.689, 0.772, respectively) and predictive abilities (r2pred = 0.780, 0.892, respectively). As a result, the design of five new compounds (T1–T5) based on the Isatin moiety, which exhibited remarkable inhibitory activity, has successfully been accomplished. Accordingly, molecular docking and molecular dynamics (MD) simulations of 100 ns have been utilized to examine the interaction mechanism and conformational changes of the newly designed compounds at the binding site of BCR‐ABL tyrosine kinase. MD simulation revealed that both compounds T1 and T2 formed stable complexes with BCR‐ABL. Additionally, the assessment of the in‐silico pharmacokinetic parameters indicates favorable ADMET properties. These findings hold promise for the future development of potent BCR‐ABL tyrosine kinase inhibitors. [ABSTRACT FROM AUTHOR]

Osteosarcoma is the most common form of primary bone cancer, which primarily afflicts children and adolescents. Chemotherapy, consisting of doxorubicin, cisplatin and methotrexate (MAP) increased the 5-year osteosarcoma survival rate from 20% to approximately 60% by the 1980s. However, osteosarcoma survival rates have remained stagnant for several decades. Patients whose disease fails to respond to MAP receive second-line treatments such as etoposide and, in more recent years, the kinase inhibitor regorafenib. BCL-2 and its close relatives enforce cellular survival and have been implicated in the development and progression of various cancer types. BH3-mimetics antagonize pro-survival members of the BCL-2 family to directly stimulate apoptosis. These drugs have been proven to be efficacious in other cancer types, but their use in osteosarcoma has been relatively unexplored to date. We investigated the potential efficacy of BH3-mimetics against osteosarcoma cells in vitro and examined their cooperation with regorafenib in vivo. We demonstrated that osteosarcoma cell lines could be killed through inhibition of MCL-1 combined with BCL-2 or BCL-xL antagonism. Inhibition of MCL-1 also sensitized osteosarcoma cells to killing by second-line osteosarcoma treatments, particularly regorafenib. Importantly, we found that inhibition of MCL-1 with the BH3-mimetic S63845 combined with regorafenib significantly prolonged the survival of mice bearing pulmonary osteosarcoma metastases. Together, our results highlight the importance of MCL-1 in osteosarcoma cell survival and present a potential therapeutic avenue that may improve metastatic osteosarcoma patient outcomes. [ABSTRACT FROM AUTHOR]

Introduction: The serine/threonine kinase 17B (STK17B) is involved in setting the threshold for T cell activation and its absence sensitizes T cells to suboptimal stimuli. Consequently, STK17B represents an attractive potential target for cancer immunotherapy. Methods: To assess the potential of STK17B as an immuno-oncology target, we developed potent and selective tool compounds from starting points in Blueprint Medicines Corporation's proprietary kinase inhibitor library. To characterize these molecules, enzyme and cellular assays for STK17A and STK17B were established to drive chemistry optimization. Mass spectrometry-based phosphoproteomics profiling with tool inhibitors led to the identification of Ser19 on myosin light chain 2 as STK17B substrate, which is then developed into a flow cytometry-based pharmacodynamic readout of STK17B inhibition both in vitro and in vivo. Results: In a mouse T cell activation assay, STK17B inhibitors demonstrated the ability to enhance interleukin-2 (IL-2) production. Similarly, treatment with STK17B inhibitors resulted in stronger cytokine secretion in human T cells activated using a T cell bispecific antibody. Subsequent chemistry optimization led to the identification of a highly selective and orally bioavailable tool compound, BLU7482. In vivo , STK17B inhibition led to dose-dependent modulation of myosin light chain 2 phosphorylation and enhanced priming of naïve T cells, as determined by upregulation of CD69, IL-2 and interferon-γ secretion. In line with increased T cell activation, treatment with STK17B inhibitor enhanced antitumor activity of anti–PD-L1 antibody in the MCA205 model. Conclusions: In summary, we successfully identified and optimized STK17B kinase inhibitors which led to increased T cell responses in vitro and in vivo. This allowed us to evaluate the potential of STK17B inhibition as an approach for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: This review highlights the recent advances in the development and application of dual function kinase inhibitors that also bear fluorescent properties (fluorescent kinase inhibitors), thus can be used as theranostics in the field of cancer. This is a rapidly growing field with significant potential for cancer therapy and diagnosis. This work mainly focuses on the key design principles that guide the development of these multifunctional compounds, emphasizing the integration of essential components such as the kinase cytotoxic warhead, the fluorophore, the linkers, and additional modular elements to enhance the efficacy of the final assembled compound. We anticipate this review to propel the advancement of this field by improving the understanding of the design principles and ultimately leading to the development of more effective tools for the concurrent diagnosis and treatment of cancer. Kinase inhibitors are potent therapeutic agents in cancer treatment, but their effectiveness is frequently restricted by the inability to image the tumor microenvironment. To address this constraint, kinase inhibitor–fluorophore conjugates have emerged as promising theranostic agents, allowing for simultaneous cancer diagnosis and treatment. These conjugates are gaining attention for their ability to visualize malignant tissues and concurrently enhance therapeutic interventions. This review explores the design principles governing the development of multimodal inhibitors, highlighting their potential as platforms for kinase tracking and inhibition via bioimaging. The structural aspects of constructing such theranostic agents are critically analyzed. This work could shed light on this intriguing field and provide adequate impetus for developing novel theranostic compounds based on small molecule inhibitors and fluorophores. [ABSTRACT FROM AUTHOR]

The cell cycle is driven by cyclin‐dependent kinases (Cdks). The decision whether the cell cycle proceeds is made during G1 phase, when Cdk4/6 functions. Cyclin‐dependent kinase inhibitor 2 (Cdkn2) is a specific inhibitor of Cdk4/6, and their interaction depends on D84 in Cdkn2 and R24/31 in Cdk4/6. This knowledge is based mainly on studies in mammalian cells. Here, we comprehensively analyzed Cdk4/6 and Cdkn2 in invertebrates and found that Cdk4/6 was present in most of the investigated phyla, but the distribution of Cdkn2 was rather uneven among and within the phyla. The positive charge of R24/R31 in Cdk4/6 was conserved in all analyzed species in phyla with Cdkn2. The presence of Cdkn2 and the conservation of the positive charge were statistically correlated. We also found that Cdkn2 has been tightly linked to Fas associated factor 1 (Faf1) during evolution. We discuss potential interactions between Cdkn2 and Cdk4/6 in evolution and the possible cause of the strong conservation of the microsynteny. [ABSTRACT FROM AUTHOR]

Objective: The efficacy of Janus kinase inhibitors (JAKi) in rheumatoid arthritis (RA) has been clearly shown. However, information on comparative drug retention rates (DRRs) of different JAKi is heterogeneous. The aim of this study was to compute and compare DRRs of different JAKi in a large cohort of RA patients. Method: Patients with RA treated with at least one JAKi and followed up at our centre were retrospectively identified. DRRs of each JAKi were computed at 24 months. The association of baseline features with drug persistence was tested. Variations in 28-joint Disease Activity Score–C-reactive protein (DAS28-CRP) and Clinical Disease Activity Index (CDAI) scores between baseline and 12 months were analysed. Results: The study included 365 patients, with a total of 463 therapy courses. Tofacitinib was the most prescribed JAKi (33%), followed by baricitinib (25%), upadacitinib (24%), and filgotinib (21%). The mean treatment duration was 24 ± 17 months, with a maximum of 70 months. At 24 months, the overall DRR was 86%. DRRs were not significantly different across different JAKi. The only baseline predictor of treatment discontinuation was previous treatment with a biological disease-modifying anti-rheumatic drug (bDMARD) (hazard ratio 1.65, 95% confidence interval 1.08–2.53; p = 0.021). There were significant reductions in DAS28-CRP and CDAI 1 year after treatment start. Conclusions: In our large, monocentric cohort, the overall 24 month DRR for JAKi was greater than 80%. No significant differences in retention were found among different JAKi. Persistence was lower in patients who had previously been treated with other bDMARDs. [ABSTRACT FROM AUTHOR]

The crystal structure of the intracellular domain of transforming growth factor β type I receptor (TβR1) in complex with the competitive inhibitor SB505124 is presented. The study provides insights into the structure and function of TβR1 in complex with SB505124, and as such offers molecular‐level understanding of the inhibition of this critical signalling pathway. The potential of SB505124 as an avenue for therapy in cancer treatment is discussed on basis of the results. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to analyze the clinical efficacy of JAK inhibitors in difficult-to-treat rheumatoid arthritis (D2TRA) and non-D2TRA patients and evaluate the factors influencing their efficacy using real-world data. Method: Here, 159 JAK inhibitor-treated patients with rheumatoid arthritis were categorized into D2TRA and non-D2TRA groups. Data including the Clinical Disease Activity Index (CDAI) at initiation and 6 months after drug administration, drug retention months, and reason for discontinuation due to toxic adverse events were collected. Results: The retention rates at 6 months were 64.0% (D2TRA) and 78.4% (non-D2TRA) and were significantly different between the two groups (p = 0.030). The discontinuation rate owing to toxic adverse events significantly differed between the two groups (p = 0.030). The CDAI-low disease activity (LDA) rates differed significantly between the two groups (non-D2TRA, 62.3%; D2TRA, 34%; p < 0.001). CDAI-LDA achievement at 6 months after drug introduction was significantly associated with the number of times that biologic and/or targeted synthetic disease-modifying anti-rheumatic drugs were previously used and the CDAI at baseline in all patients treated with JAK inhibitors. However, no predictive factors were identified for D2TRA patients treated with JAK inhibitors. Conclusion: Compared to non-D2TRA patients, D2TRA patients demonstrated significantly lower drug retention rates, CDAI-LDA achievement rates, and safety of JAK inhibitors. No significant predictive factor for CDAI-LDA achievement 6 months after drug introduction was detected in D2TRA patients. Key Points • The retention of JAK inhibitors were significantly lower for the treatment of D2TRA patients in comparison with non-D2TRA patients. • The efficacy and safety of JAK inhibitors were significantly lower for the treatment of D2TRA patients. • Number of previous uses of b/tsDMARDs and CDAI at baseline were identified as the predictive factors for resistance to CDAI-LDA achievement to JAK inhibitor treatment. • No significant predictive factor for CDAI-LDA achievement 6 months after drug introduction was detected in D2TRA patients. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a complex multi-organ autoimmune disease marked by the production of autoantibodies against nuclear structures, formation of immune complexes, and chronic inflammation triggered by their tissular deposition. SLE is characterized by alternating periods of relapse and remission and each flare has the potential to cause new organ damage related to either the disease process or the medication toxicity. Despite remarkable progress across its multiple domains, SLE is still an area with many unmet needs, calling for innovative and practical solutions. The efforts of the drug development programme in lupus have led to considerable growth in the last decade, owing to the approval of belimumab, anifrolumab, and voclosporin. The increasing understanding of the pathogenesis of the disease has enabled the exploration of novel therapeutic strategies. New discoveries in the intricate cytokine kaleidoscope of lupus have made the concept of targeted therapy an attractive and promising research focus. JAK inhibitors are oral targeted therapies approved for a wide variety of diseases across the Rheumatology, Gastroenterology, Dermatology, and Haematology fields. Multiple JAKis are currently being investigated in SLE. This paper aims to summarize existing data coming from both clinical trials and case reports regarding the use of JAK inhibitors in SLE. [ABSTRACT FROM AUTHOR]

Summary: Background: Several new treatments including small molecules and biologics have been approved for the treatment of inflammatory bowel diseases in recent years. Clinicians and patients now have a wide variety of therapeutic options to choose from and these novel therapies provide several advantages including oral administration, lower immunogenicity, better selectivity and arguably better safety profiles. An increase in treatment options has increased the complexity of decision‐making. Both patients and clinicians have had to become rapidly familiar with efficacy of new medications balanced against a range of pre‐initiation requirements, dosing schedules and adverse event profiles. Aims: To provide a simple guide to practising clinicians on recently approved and emerging therapies and address key challenges around treatment strategies such as optimal sequencing and timing of treatment. Methods: We comprehensively searched the published literature and major conference abstracts to identify phase III placebo‐controlled and active comparator trials for Crohn's disease and ulcerative colitis. Results: Data for recently approved therapies including selective Janus kinase inhibitors, sphingosine‐1 receptor modulators and p19 interleukin (IL)‐23 inhibitors have demonstrated improved patient outcomes in both Crohn's disease and ulcerative colitis. Further comparative head‐to‐head studies have improved our understanding of when and how to optimally use newer therapies, specifically for IL‐23 inhibitors. Data for emerging treatment options and novel treatment strategies such as early effective treatment, combinations of treatments and implications for sequencing are continuing to transform IBD care continually. Conclusions: Recently approved novel therapies have expanded the range of medical options available to treat IBD. However, further data from long‐term extension studies, real‐world studies and head‐to‐head trials are warranted to better inform the long‐term safety and optimal sequencing of treatments for patients living with IBD. [ABSTRACT FROM AUTHOR]

Objectives: There is limited data on the incidence, prevalence, and treatments for myelofibrosis (MF) in Germany. This retrospective study examined claims data from 3.3 million insured individuals, spanning from 2010 to 2021. Methods: Four sensitivity scenarios were explored to identify cases of MF. Point prevalence and cumulative incidence of MF were determined as of December 31, 2021, and within 2021, respectively. A cross‐sectional analysis used the main scenario definition of MF to identify cases and evaluate the period prevalence of patients receiving treatment for symptoms and/or splenomegaly, including first‐line (1L) Janus kinase inhibitor (JAKi), second‐line, or further (2L+) MF‐related treatment therapies during 2021. The prevalence of anemia treatment was also reported. Results: The estimated standardized point prevalence of MF on December 31, 2021, was 9.9–12.4 cases per 100 000 persons, and cumulative incidence in 2021 was 1.2–1.8 cases per 100 000 persons. Standardized period prevalence in 2021 for MF patients receiving 1L JAKi and/or 2L+ MF‐related treatment was 4.0 cases per 100 000. Among these patients, 47.1%–53.7% required treatment for anemia, resulting in a period prevalence of 1.9–2.2 cases per 100 000 individuals. Conclusion: The data reveal gaps in MF treatments and the need to improve patient quality of life. [ABSTRACT FROM AUTHOR]

Upadacitinib, a selective Janus kinase inhibitor, is the first orally administered therapy approved for the treatment of Crohn's disease (CD). This work characterized the pharmacokinetics of upadacitinib in CD patients and evaluated the relationships between upadacitinib steady‐state plasma exposures and efficacy as well as safety parameters during the 12‐week induction and the 52‐week maintenance periods, to provide dosing recommendations for the treatment of CD. Upadacitinib pharmacokinetics in CD patients administered the extended‐release formulation were consistent with patient populations in other approved indications. None of the evaluated CD‐specific patient characteristics (e.g., disease location and prior gastrointestinal surgeries) had a meaningful impact on upadacitinib pharmacokinetics. Exposure–response analyses during 12‐week induction treatment showed that response across all evaluated efficacy end points were approaching a plateau at median plasma exposures associated with 45 mg QD. Analyses for the maintenance period demonstrated that 30 mg QD is predicted to provide an additional 8% to 10% benefit for endoscopic response and endoscopic remission compared with 15 mg QD in patients who failed biologics. The analyses for safety showed a statistically significant relationship between increasing upadacitinib plasma exposures and the percentage of patients experiencing >2 g/dL decrease in hemoglobin from Baseline during induction and showed shallow relationships for serious infections and herpes zoster during the maintenance period. These results demonstrated adequate absorption of the extended‐release formulation of upadacitinib in CD patients. The exposure–response analyses confirmed that 45 mg QD dose maximized efficacy as induction treatment and supported the selection of 15 mg QD or 30 mg QD as the maintenance doses. [ABSTRACT FROM AUTHOR]

This study evaluated the in vitro effectiveness of anti-cryptosporidial agents nitazoxanide, halofuginone, the pyrazolopyridine analog KDU731, and paromomycin (PMC) in combating the significant zoonotic pathogen Cryptosporidium parvum. The study utilized HCT-8 host cells to culture C. parvum and fluorescent microscopy/quantitative PCR (qPCR) for detecting parasitic growth. The efficacy of the compounds was assessed by calculating their inhibitory concentrations (IC) against the total growth of C. parvum at 48 h post-infection. The study further investigated the impact of these compounds on early parasitophorous vacuole (PV) formation, merozoite egress, host cell viability, and cell growth cycle. KDU731 displayed the most promising profile, with low nanomolar (102 nM ± 2.28) activity and negligible host cell toxicity. This study offers new insights into the relative efficacy and safety of various anti-cryptosporidial compounds, highlighting their stage-specific effects on C. parvum and the consequential impacts on host cells. Identifying safe and effective anti-cryptosporidial agents contributes significantly to the One Health approach, which emphasizes the importance of integrated strategies in controlling zoonotic diseases. [ABSTRACT FROM AUTHOR]

Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA). These post hoc exposure–response (E–R) analyses of pooled data from two Phase 3 studies (NCT01877668 and NCT01882439) characterized the relationships between tofacitinib exposure and efficacy (American College of Rheumatology [ACR] criteria), and changes in hemoglobin (Hgb) in patients with PsA. Efficacy data for the proportion of patients receiving tofacitinib 5 or 10 mg twice daily, or placebo, achieving ACR ≥20%, ≥50%, or ≥70% response criteria (ACR20, ACR50, and ACR70, respectively) at Month 3, were modeled jointly using a four‐category ordered categorical exposure–response model (ACR20 non‐responder, ACR20 responder but not ACR50 responder, ACR50 responder but not ACR70 responder, and ACR70 responder). A maximum drug effect (Emax) model (using average concentrations of tofacitinib at steady state [Cavg]) adequately described the exposure–ACR response rate relationship. Model‐predicted response rates for tofacitinib 5 and 10 mg twice daily were 51% and 58%, respectively, for ACR20; 29% and 36% for ACR50; and 15% and 20% for ACR70. The E–R relationship between tofacitinib exposure and changes in Hgb was assessed using an indirect response model, which generally predicted Hgb concentration–time profiles across treatments well. The proportions of patients experiencing a decrease in Hgb of >2 g/dL were similar with tofacitinib 5 mg twice daily or placebo. These results were generally consistent with previous analyses in rheumatoid arthritis and psoriasis, and support the use of tofacitinib 5 mg twice daily for active PsA. [ABSTRACT FROM AUTHOR]

Structure-based virtual screening (SBVS) is a crucial computational approach in drug discovery, but its performance is sensitive to structural variations. Kinases, which are major drug targets, exemplify this challenge due to active site conformational changes caused by different inhibitor types. Most experimentally determined kinase structures have the DFGin state, potentially biasing SBVS towards type I inhibitors and limiting the discovery of diverse scaffolds. We introduce a multi-state modeling (MSM) protocol for AlphaFold2 (AF2) kinase structures using state-specific templates to address these challenges. Our comprehensive benchmarks evaluate predicted model qualities, binding pose prediction accuracy, and hit compound identification through ensemble SBVS. Results demonstrate that MSM models exhibit comparable or improved structural accuracy compared to standard AF2 models, enhancing pose prediction accuracy and effectively capturing kinase-ligand interactions. In virtual screening experiments, our MSM approach consistently outperforms standard AF2 and AF3 modeling, particularly in identifying diverse hit compounds. This study highlights the potential of MSM in broadening kinase inhibitor discovery by facilitating the identification of chemically diverse inhibitors, offering a promising solution to the structural bias problem in kinase-targeted drug discovery. [ABSTRACT FROM AUTHOR]

We previously showed that the anticancer drug imatinib mesylate (IMT, trade name: Gleevec) and a chemically distinct compound, DV2-103 (a kinase-inactive derivative of the potent Abl and Src kinase inhibitor, PD173955) lower Aβ levels at low micromolar concentrations primarily through a lysosome-dependent mechanism that renders APP less susceptible to proteolysis by BACE1 without directly inhibiting BACE1 enzymatic activity, or broadly inhibiting the processing of other BACE1 substrates. Additionally, IMT indirectly inhibits γ-secretase and stimulates autophagy, and thus may decrease Aβ levels through multiple pathways. In two recent studies we demonstrated similar effects on APP metabolism caused by derivatives of IMT and DV2-103. In the present study, we synthesized and tested radically altered IMT isomers (IMTi's) that possess medium structural similarity to IMT. Independent of structural similarity, these isomers manifest widely differing potencies in altering APP metabolism. These will enable us to choose the most potent isomers for further derivatization. [ABSTRACT FROM AUTHOR]

Pim-1 kinase, a serine/threonine kinase, is often overexpressed in various cancers, contributing to disease progression and poor prognosis. In this study, we explored the potential of flavonoids as inhibitors of Pim-1 kinase using a combination of molecular docking and steered molecular dynamics (SMD) simulations. Our docking studies revealed two main binding orientations for the flavonoid molecules. The SMD simulations showed that the binding mode with higher pulling forces was linked to stronger inhibitory activity, with a strong positive correlation (R2 = 0.92) between pulling forces and IC50 values. Quercetin stood out as the most potent inhibitor, showing a pulling force of about 820 pN and an IC_(5) 0 of less than 6 µM. Further dynamic simulations indicated that quercetin's hydroxyl groups at the C3, C-5 and C-7 positions formed stable hydrogen bonds with key residues GLU-121, Leu-44 and Val-126, respectively enhancing its binding stability and effectiveness. Our results emphasized the critical role of the hydroxyl group at the C-3 position, which plays a pivotal function in effectively anchoring these molecules in the active site of Pim-1 kinase. Principal component analysis (PCA) of Pim-1 kinase's conformational changes revealed that potent inhibitors like quercetin, galangin, and kaempferol significantly restricted the enzyme's flexibility, suggesting potential inhibitory effect. These findings provide insights into the structural interactions between flavonoids and Pim-1 kinase, offering a foundation for future experimental investigations. However, further studies, including in vitro and in vivo validation, are necessary to assess the pharmacological relevance and specificity of flavonoids in cancer therapy. [ABSTRACT FROM AUTHOR]

ABSTRACT Spleen volume reduction (SVR) is a key endpoint in inhibitors of Janus kinase (JAK) inhibitor studies. Retrospective analyses have demonstrated an association between SVR and improved overall survival (OS) among patients treated with ruxolitinib with a platelet count > 100 × 109/L. Whether this association occurs in patients with thrombocytopenia is unclear. Pacritinib, a JAK2/IRAK1/ACVR1 inhibitor, demonstrated improved SVR versus best available therapy (BAT [best available therapy]; including ruxolitinib) in patients with myelofibrosis and platelet counts ≤ 100 × 109/L in the PERSIST‐2 study. Patients on study at the start of the 12‐week SVR window on pacritinib 200 mg twice daily or BAT were included. OS was evaluated among SVR responders versus non‐responders using different SVR thresholds (≥ 35%, ≥ 20%, ≥ 10%, and > 0%). Among patients on pacritinib (n = 89), SVR ≥ 10% demonstrated the greatest separation in OS curves between responders and non‐responders (HR, 0.00; 95% CI, 0.00–0.14; p < 0.01), though SVR ≥ 0% and SVR ≥ 20% were also associated with improved OS. No SVR threshold conferred OS benefit on BAT (n = 84), including ruxolitinib (n = 39). In patients with myelofibrosis and platelets ≤ 100 × 109/L, achieving SVR on pacritinib, but not BAT (including ruxolitinib), was associated with significant OS benefit, suggesting that pacritinib may offer a unique survival advantage in patients with myelofibrosis and thrombocytopenia who achieve any SVR.Trial Registration: ClinicalTrials.gov number: NCT02055781 [ABSTRACT FROM AUTHOR]

Background: Venous thromboembolism (VTE) risk is higher among patients with non–small cell lung cancer (NSCLC) and specific subgroups, including the elderly, but little is known about the VTE risk of different generations of epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR‐TKIs) and whether the risk differs by demographic characteristics. This study aims to compare the risk of VTE (deep venous thromboembolism [DVT]; pulmonary embolism [PE]) between a third‐generation EGFR‐TKI and first/second‐generation EGFR‐TKIs and stratify VTE risk by sex, age, and race/ethnicity in third‐generation EGFR‐TKI users. Methods: Via the 2006–2019 Surveillance, Epidemiology, and End Results–Medicare database, this retrospective cohort study included older patients (aged ≥65 years) with advanced NSCLC who initiated on a third‐generation EGFR‐TKI (n = 493) and first/second‐generation EGFR‐TKIs (n = 1036). We estimated the hazard ratio (HR) and its 95% confidence interval (95% CI) with the Cox proportional hazards model. Results: A third‐generation EGFR‐TKI had a significantly higher VTE risk than first/second‐generation EGFR‐TKIs (HR, 1.26 [95% CI, 1.01–1.57]; p =.037), with an elevated risk in males (HR, 2.16 [95% CI, 1.47–3.19]; p <.001), patients aged ≥75 years (HR, 1.38 [95% CI, 1.04–1.83]; p =.026), and non‐Hispanic Whites (HR, 1.46 [95% CI, 1.10–1.95]; p =.010). Males consistently showed a significantly higher risk of DVT (HR, 2.49 [95% CI, 1.29–4.80]; p =.007) and PE (HR, 2.00 [95% CI, 1.29–3.11]; p =.002). A significantly higher risk of DVT (HR, 1.54 [95% CI, 1.00–2.37]; p =.050) and PE (HR, 1.47 [95% CI, 1.06–2.05]; p =.021) was shown in patients aged ≥75 years and non‐Hispanic Whites, respectively. Among third‐generation EGFR‐TKI users, non‐Hispanic Whites had a significantly higher risk of VTE (HR, 2.04 [95% CI, 1.03–4.02]; p =.041) and PE (HR, 2.88 [95% CI, 1.24–6.70]; p =.014) than non‐Hispanic Asian/Pacific Islanders. Conclusions: Close monitoring of VTE events in high‐risk patients is essential to promote early diagnosis and treatment. In older patients with non–small cell lung cancer, those treated with osimertinib (a third‐generation epidermal growth factor receptor–tyrosine kinase inhibitor [EGFR‐TKI]) had a significantly higher risk of venous thromboembolism (VTE) than those treated with traditional EGFR‐TKIs. The risk was elevated in patients who were male, aged ≥75 years, and non‐Hispanic White, which raises the need for close monitoring of VTE when using osimertinib. [ABSTRACT FROM AUTHOR]

The protein kinases DYRK1A and DYRK1B are pivotal regulators of cell cycle progression by promoting cell cycle exit into quiescence. DYRK1B appears to play a more important role in cancer cell quiescence than DYRK1A, as evidenced by its overexpression or copy number variations in human tumour samples. Nonetheless, the stimuli driving DYRK1B upregulation and the potential divergence in expression patterns between DYRK1A and DYRK1B remain largely elusive. In the present study, we scrutinized the regulatory pathways modulating DYRK1B expression relative to DYRK1A in PANC-1 and A549 cancer cell lines across varying conditions. Serum deprivation, pharmacological mTOR inhibition and increased cell density resulted in the differential upregulation of DYRK1B compared to DYRK1A. We then aimed to assess the role of protein kinases MST1 and MST2, which are key transmitters of cell density dependent effects. Unexpectedly, exposure to the MST1/2 inhibitor XMU-MP-1 resulted in increased DYRK1B levels in A549 cells. Further investigation into the off-target effects of XMU-MP-1 unveiled the inhibition of Aurora kinases (AURKA and AURKB) as a potential causative factor. Consistently, AURK inhibitors VX-680 (tozasertib), MLN8237 (alisertib), AZD1152-HQPA (barasertib) resulted in the upregulation of DYRK1B expression in A549 cells. In summary, our findings indicate that the expression of DYRK1A and DYRK1B is differentially regulated in cancer cells and reveal that the kinase inhibitor XMU-MP-1 increases DYRK1B expression likely through off target inhibition of Aurora kinases. [ABSTRACT FROM AUTHOR]

Background: The treatment of head and neck tumors remains a challenge due to their reduced radiosensitivity. Small molecule kinase inhibitors (smKI) that inhibit the DNA damage response, may increase the radiosensitivity of tumor cells. However, little is known about how the immunophenotype of the tumor cells is modulated thereby. Therefore, we investigated whether the combination of ATM or ATR inhibitors with hypo-fractionated radiotherapy (RT) has a different impact on the expression of immune checkpoint markers (extrinsic), the release of cytokines or the transcriptome (intrinsic) of head and neck squamous cell carcinoma (HNSCC) cells. Methods: The toxic and immunogenic effects of the smKI AZD0156 (ATMi) and VE-822 (ATRi) in combination with a hypo-fractionated scheme of 2x5Gy RT on HPV-negative (HSC4, Cal-33) and HPV-positive (UM-SCC-47, UD-SCC-2) HNSCC cell lines were analyzed as follows: cell death (necrosis, apoptosis; detected by AnxV/PI), expression of immunostimulatory (ICOS-L, OX40-L, TNFSFR9, CD70) and immunosuppressive (PD-L1, PD-L2, HVEM) checkpoint marker using flow cytometry; the release of cytokines using multiplex ELISA and the gene expression of Cal-33 on mRNA level 48 h post-RT. Results: Cell death was mainly induced by the combination of RT with both inhibitors, but stronger with ATRi. Further, the immune phenotype of cancer cells, not dying from combination therapy itself, is altered predominantly by RT+ATRi in an immune-stimulatory manner by the up-regulation of ICOS-L. However, the analysis of secreted cytokines after treatment of HNSCC cell lines revealed an ambivalent influence of both inhibitors, as we observed the intensified secretion of IL-6 and IL-8 after RT+ATRi. These findings were confirmed by RNAseq analysis and further the stronger immune-suppressive character of RT+ATMi was enlightened. We detected the down-regulation of a central protein of cytoplasmatic sensing pathways of nucleic acids, RIG-1, and found one immune-suppressive target, EDIL3, strongly up-regulated by RT+ATMi. Conclusion: Independent of a restrictive toxicity, the combination of RT + either ATMi or ATRi leads to comprehensive and immune-modulating alterations in HNSCC. This includes pro-inflammatory signaling induced by RT + ATRi but also anti-inflammatory signals. These findings were confirmed by RNAseq analysis, which further highlighted the immune-suppressive nature of RT + ATMi. [ABSTRACT FROM AUTHOR]

Cancer is a devastating disease, with female breast cancer becoming the leading cause of global cancer morbidity. Sorafenib is a multiple kinase inhibitor, and exhibits activity against a wide spectrum of tumor types, however, in some cases it proves insufficient. Synthesis of sorafenib analogs can be an efficient way to discover potent cancer therapeutic agents. In this work, we intended to design sorafenib analogs and determine their antiproliferative activity against five cancer cell lines (A549, HepG2, HCT116, MDA‐MB‐231, and PC‐3) using MTS method. As a result, we synthesized a sorafenib analog 1 A and its base‐promoted arranged compound 1 A2. Their in‐vitro cytotoxicity and potencies in the epidermal growth factor receptor (EGFR) inhibition study revealed that compound 1 A displayed higher inhibition activity than cisplatin in MDA‐MB‐231 (breast cancer) cells with an IC50 value of 16.18±1.42 μM. The structure of 1 A2 was explicitly confirmed by the single‐crystal X‐ray diffraction analysis. [ABSTRACT FROM AUTHOR]

Background: Inorganic polyphosphate (polyP)-targeted polyphosphate kinase 1 (PPK1) has attracted much attention by virtue of its importance in bacterial pathogenicity and persistence, as well as its exclusive presence in microorganisms. However, only very few drugs have been found to be efficacious in inhibiting the Acinetobacter baumannii (A. baumannii) PPK1 protein. Results: In this study, we identified Scutellarein (Scu), a potent PPK1 inhibitor that could significantly influence PPK1-regulated motility, biofilm formation, and bacterial persistence, which was further validated by the results of transcriptome analysis. Mechanistic explorations revealed that Scu achieved its enzyme inhibitory activity predominantly through direct engagement with the active center of PPK1. Moreover, the survival rate of Galleria mellonella larvae was increased by about 35% with 20 mg/kg of Scu treatment. The remarkable therapeutic benefits of Scu were also observed in the mouse pneumonia model, shown mainly by reduced bacterial colonization, pathological lesions, and inflammatory factors. Conclusion: Our results revealed that Scu could attenuate the pathogenicity and persistence of A. baumannii by interfering with its important kinase PPK1. [ABSTRACT FROM AUTHOR]

Acute severe ulcerative colitis (ASUC) is a medical emergency that affects approximately 25% of patients with ulcerative colitis at some point in time in their lives. Outcomes of ASUC are highly variable. Approximately 30% of patients do not respond to corticosteroids and up to 50% of patients do not respond to rescue therapy (infliximab or cyclosporin) and require emergency colectomy. Data are emerging on infliximab dosing strategies, use of cyclosporin as a bridge to slower acting biologic agents and Janus kinase inhibition as primary and sequential therapy. In this review, we outline contemporary approaches to clinical management of ASUC in the setting of failure to respond to traditional rescue therapies. [ABSTRACT FROM AUTHOR]

Splicing modulation by a small compound offers therapeutic potential for diseases caused by splicing abnormality. However, only a few classes of compounds that can modulate splicing have been identified. We previously identified BAY61‐3606, a multiple kinase inhibitor, as a compound that relaxes the splicing fidelity at the 3′ splice site recognition. We have also reported the synthesis of derivatives of BAY61‐3606. In this study, we tested those compounds for their splicing modulation capabilities and identified two contrasting compounds. These compounds were further investigated for their effects on the whole transcriptome, and analysis of changes in transcription and splicing revealed that the highly active derivative in the splicing reporter assay also showed significantly higher activity in modulating the splicing of endogenously expressed genes. Particularly, cassette exon inclusion was highly upregulated by this compound, and clustering analysis revealed that these effects resembled those in splicing factor 3b subunit 1 (SF3B1) K700E mutant cells but contrasted with those of the splicing inhibitor H3B‐8800. Additionally, a group of serine/arginine‐rich (SR) protein genes was identified as representatively affected, likely via modulation of poison exon inclusion. This finding could guide further analysis of the mode of action of these compounds on splicing, which could be valuable for developing drugs for diseases associated with splicing abnormalities. [ABSTRACT FROM AUTHOR]

Because host kinases are key regulators of multiple signaling pathways in response to viral infections, we previously screened a kinase inhibitor library using rhabdomyosarcoma cells and human intestinal organoids in parallel to identify potent inhibitors against EV-A71 infection. We found that Rho-associated coiled-coil-containing protein kinase (Rock) inhibitor efficiently suppressed the EV-A71 replication and further revealed Rock1 as a novel EV-A71 host factor. In this study, subsequent analysis found that a variety of vascular endothelial growth factor receptor (VEGFR) inhibitors also had potent antiviral effects. Among the hits, Pazopanib, with a selectivity index as high as 254, which was even higher than that of Pirodavir, a potent broad-spectrum picornavirus inhibitor targeting viral capsid protein VP1, was selected for further analysis. We demonstrated that Pazopanib not only efficiently suppressed the replication of EV-A71 in a dose-dependent manner, but also exhibited broad-spectrum anti-enterovirus activity. Mechanistically, Pazopanib probably induces alterations in host cells, thereby impeding viral genome replication and transcription. Notably, VEGFR2 knockdown and overexpression suppressed and facilitated EV-A71 replication, respectively, indicating that VEGFR2 is a novel host dependency factor for EV-A71 replication. Transcriptome analysis further proved that VEGFR2 potentially plays a crucial role in combating EV-A71 infection through the TSAd-Src-PI3K-Akt pathway. These findings expand the range of potential antiviral candidates of anti-enterovirus therapeutics and suggest that VEGFR2 may be a key host factor involved in EV-A71 replication, making it a potential target for the development of anti-enterovirus therapeutics. [ABSTRACT FROM AUTHOR]

Introduction: Rapid progress made in the management of atopic dermatitis (AD) in recent years and the differences in patient journey between Asian and non-Asian populations call for a review of current atopic dermatitis landscape in Asia. Methods: A roundtable meeting with nine regional dermatological experts was held in June 2023 to discuss the optimal management approaches for moderate-to-severe AD, focusing on the use of advanced therapies. Results: Disease burden on patients' quality of life, treatment adherence, and financial constraints were identified as major concerns when managing patients with moderate-to-severe AD in parts of Asia. It was agreed that the Hanifin and Rajka's criteria or the UK Working Party's Diagnostic Criteria for Atopic Dermatitis can be used to guide the clinical diagnosis of AD. Meanwhile, patient-reported outcome scales including the Dermatology Life Quality Index and Atopic Dermatitis Control Tool can be used alongside depression monitoring scales to monitor treatment outcomes in patients with AD, allowing a better understanding for individualized treatment. When managing moderate-to-severe AD, phototherapy should be attempted after failure with topical treatments, followed by conventional disease-modifying antirheumatic drugs and, subsequently, biologics or Janus kinase inhibitors. Systemic corticosteroids can be used as short-term therapy for acute flares. Although these advanced treatments are known to be effective, physicians have to take into consideration safety concerns and limitations when prescribing these treatments. Conclusions: Treatments in AD have evolved and its management varies country by country. Unique challenges across Asian countries necessitate a different management approach in Asian patients with AD. [ABSTRACT FROM AUTHOR]

Canine malignant melanoma (CMM) is highly aggressive and mostly located in the oral cavity. CMM is the predominant type of canine oral malignancy and shows striking homologies with human mucosal melanoma. In comparative oncology, canine oral melanomas (COMs), as spontaneous tumor models, have the potential to acquire a unique value as a translational model of rare human melanoma subtypes. This review aims to provide a comprehensive summary of targeted therapies for canine malignant melanoma and to enrich the field of comparative oncology. Following the PRISMA guidelines, a comprehensive literature search was conducted across databases for studies from 1976 to April 2024. Studies were selected based on their relevance to targeted treatments. A total of 30 studies met the inclusion criteria. Based on the treatment approaches, the studies were further categorized into immunotherapies, small molecule signaling inhibitors, indirect kinase inhibitors, and other alternative strategies. Some treatments have been shown to result in stable disease or partial response, accounting for 29% (monoclonal antibody) and 76.5% (micro-RNA therapies) in clinical trials. Moreover, in vitro experiments of small molecule inhibitors, including cell signaling inhibitors and indirect kinase inhibitors, have shown the potential to be an effective treatment option for the development of therapeutic strategies in canine malignant melanoma. The observed response in in vitro experiments of CMM (particularly the oral and certain cutaneous subtypes) to drugs used in the treatment of human melanoma underlines the resemblance to human melanoma, therefore supporting the notion that CMM may be a valuable model for understanding rare human melanoma subtypes and exploring potential therapeutic avenues in preclinical trials. Finally, this literature review serves as a valuable resource for the development of therapeutic strategies for CMM and highlights the potential for translating these findings to human cancer treatment. [ABSTRACT FROM AUTHOR]

ABSTRACT Children with severe atopic dermatitis (AD), refractory to conventional systemic treatment as well as single‐agent biologic and Janus kinase inhibitor (JAKi) such as abrocitinib, currently face a lack of treatment options. In response to this clinical conundrum, we present three cases of severe and refractory pediatric AD successfully managed with combined dupilumab and abrocitinib. These children had exhausted all conventional treatments and had undergone treatment with both dupilumab and abrocitinib individually, as well as dupilumab in conjunction with methotrexate. It was only when the combination of dupilumab and abrocitinib was introduced that they finally achieved noticeable and sustained improvements in disease control. [ABSTRACT FROM AUTHOR]

It is crucial to find optimally combined anticancer drug treatments among diverse therapeutics and deliver them simultaneously in a prolonged manner for efficient tumor therapy. In this study, we investigated the novel combined treatment strategy of doxorubicin (Dox) and TGF-β receptor 1 kinase inhibitor (SD208) through the fabrication of exosome (EXO)-immobilized porous microspheres to achieve efficient and sustained anticancer effects. The combined treatment of Dox and SD208 exhibited significant improvements in anticancer efficacy compared to Dox treatment alone in both breast cancer cells (MCF-7) and lung cancer cells (A549). After the Dox and SD208 co-encapsulated EXOs (combiEXOs; ~ 80 nm) were immobilized onto the surface of cationic porous microspheres (PM) through simple electrostatic interactions, the attached combiEXOs were released in a sustained manner over 120 h. Furthermore, combiEXOs onto PMs (PM-combiEXO) effectively induced significant apoptosis in A549 cells and suppressed the proliferation of A549 cells for 5 days with minimal toxicity to fibroblasts. Taken together, the developed PM-combiEXOs significantly improved the anticancer effects in A549 cells in a sustained manner with minimal nonspecific toxicity, demonstrating potential applicability across a wide range of cancers for diverse combined treatments with anticancer drugs. [ABSTRACT FROM AUTHOR]

Introduction: Clinical remission is the main target in the management of patients with rheumatoid arthritis (RA). However, several authors found synovitis in patients with RA in clinical remission at ultrasonography (US). Upadacitinib is a selective Janus kinase 1 inhibitor that achieved significantly higher remission rates than adalimumab and abatacept in patients with RA. Here we present the 24-week data of the UPAdacitinib Rheumatoid Arthritis REmission UltraSonography (UPARAREMUS) study. Methods: This is a longitudinal multicenter observational study, enrolling bio-naïve and bio-inadequate responder patients affected by RA. The primary endpoint was the proportion of patients achieving both clinical and US remission at week 24. The proportion of patients achieving clinical remission with different composite indexes at week 12 and 24 was also evaluated. US of four target joints (wrists and second metacarpophalangeal bilaterally) was performed at baseline and weeks 12/24, and US remission was defined as the absence of power Doppler (PD) signal ≥ 2 in one target joint, or PD ≥ 1 in two target joints. Results: After 12 weeks and 24 weeks, 40% and 63.6% of patients achieved US plus clinical remission. The following parameters were associated with US plus clinical remission: being bio-naïve and having a shorter disease duration, although at multivariate analysis significant odds ratio (OR) was found only for being bio-naïve. Conclusions: UPARAREMUS is the first study evaluating the efficacy of upadacitinib in reaching both clinical and US remission in patients with RA. At 24 weeks, 63.6% of patients reached the primary endpoint, the only baseline associated parameter was being bio-naïve. [ABSTRACT FROM AUTHOR]

Actualizar el consenso de la Sociedad Española de Reumatología (SER) sobre el uso de terapias biológicas y sintéticas dirigidas en la artritis reumatoide (AR) como medio de apoyo al clínico en sus decisiones terapéuticas. Se constituyó un panel de 13 expertos a través de convocatoria abierta en la SER. Se empleó una metodología mixta de adaptación-elaboración-actualización a partir del Documento de Consenso de la Sociedad Española de Reumatología sobre el uso de terapias biológicas en la AR publicado en 2015. Se partió de las revisiones sistemáticas (RS) de las recomendaciones de EULAR 2019, American College of Rheumatology 2021 y GUIPCAR 2017 y se actualizaron las estrategias de búsqueda de las preguntas PICO de GUIPCAR, elaborándose una RS adicional sobre enfermedad desmielinizante en relación con tratamientos biológicos y sintéticos dirigidos. Tras el análisis de la evidencia por los diferentes panelistas se consensuó en reunión presencial la redacción y el grado de acuerdo de cada una de las recomendaciones. El panel acordó 5 principios generales y 15 recomendaciones sobre el manejo de la AR. Estas incluyen aspectos como la importancia del tratamiento precoz, el objetivo terapéutico en la AR, la frecuencia de monitorización, el uso de glucocorticoides, la utilización de fármacos antirreumáticos modificadores de la enfermedad (FAME) sintéticos convencionales (FAMEsc), FAME biológicos (FAMEb) y FAME sintéticos dirigidos, así como la reducción de dosis de estos fármacos en pacientes estables. Además, en esta actualización se incluyen recomendaciones sobre el uso de FAMEb e inhibidores de Janus-kinasas en algunas situaciones clínicas especiales, como pacientes con enfermedad pulmonar, antecedente de cáncer, insuficiencia cardiaca o enfermedad desmielinizante. Esta actualización aporta recomendaciones sobre aspectos clave en el manejo de la AR con terapias biológicas y sintéticas dirigidas. To update the consensus document of the Spanish Society of Rheumatology (SER) regarding the use of targeted biological and synthetic therapies in rheumatoid arthritis (RA) with the aim of assisting clinicians in their therapeutic decisions. A panel of 13 experts was assembled through an open call by SER. We employed a mixed adaptation-elaboration-update methodology starting from the 2015 Consensus Document of the Spanish Society of Rheumatology on the use of biological therapies in RA. Starting with systematic reviews (SR) of recommendations from EULAR 2019, American College of Rheumatology 2021, and GUIPCAR 2017, we updated the search strategies for the PICO questions of GUIPCAR. An additional SR was conducted on demyelinating disease in relation to targeted biological and synthetic therapies. Following the analysis of evidence by different panelists, consensus on the wording and level of agreement for each recommendation was reached in a face-to-face meeting. The panel established 5 general principles and 15 recommendations on the management of RA. These encompassed crucial aspects such as the importance of early treatment, therapeutic goals in RA, monitoring frequency, the use of glucocorticoids, the application of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), biological DMARDs (bDMARDs), and targeted synthetic DMARDs. Additionally, recommendations on dose reduction of these drugs in stable patients were included. This update also features recommendations on the use of bDMARDs and Janus Kinase inhibitors in some specific clinical situations, such as patients with lung disease, a history of cancer, heart failure, or demyelinating disease. This update provides recommendations on key aspects in the management of RA using targeted biological and synthetic therapies. [ABSTRACT FROM AUTHOR]

Human epidermal growth factor receptor 2 (HER2) is known for its oncogenic activities in diverse cancers, including non-small cell lung cancer (NSCLC). However, the prevalence of HER2 alterations in Malaysian NSCLC patients remains unreported. This study examined the prevalence and characteristics of HER2 mutations and amplification in a Malaysian cohort. Additionally, a systematic review was conducted to evaluate the global prevalence of HER2 alterations in NSCLC, as well as the efficacy of HER2-targeted therapies observed in clinical trials. NSCLC tumour samples received from October 2019 to December 2022 for next-generation sequencing diagnostics were included in the retrospective analysis. In this patient cohort, HER2 alteration was present in 5.8% of patients; 3.9% had HER2 mutations, 1.5% had HER2 amplifications and 0.4% were both HER2-mutated and amplified. HER2 exon 20 insertions were the most common HER2 variants, detected in 47/59 (79.7%) of HER2-mutated patients. Among cases with HER2 exon 20 insertions, the Y772&lowbar;A775dup variant was found in 34 patient samples. HER2-mutated patients were significantly younger than non-HER2-mutants (61 versus 64 years old; p = 0.046) and were inclined to be female and never-smokers, albeit not statistically significant. Patients with HER2 amplification were more likely to have progressed post-tyrosine kinase inhibitor therapy (p = 0.015). The systematic review highlighted a global variation in the prevalence of HER2 alterations in NSCLC, ranging from 0.3% to 9.1% for mutations and 0.2% to 19% for amplification. Finally, phase II clinical trials involving HER2-altered NSCLC patients demonstrated promising treatment outcomes with trastuzumab deruxtecan, trastuzumab emtansine, pyrotinib, pyrotinib + apatinib and trastuzumab + pertuzumab + docetaxel. In conclusion, the prevalence of HER2 alteration among Malaysian NSCLC patients falls within the global range. A systematic review of clinical trials revealed promising treatment outcomes and Malaysian NSCLC patients with HER2 alterations are anticipated to similarly benefit from HER2-targeted therapies. [ABSTRACT FROM AUTHOR]

Context Lenvatinib is approved for the treatment of radioiodine-refractory differentiated thyroid cancer (RR-DTC). The definition of predictive factors of survival is incomplete. Objective To identify pre- and posttreatment survival predictors in a real-life cohort of RR-DTC treated with lenvatinib. Design Multicenter, retrospective, cohort study. Setting 3 Italian thyroid cancer referral centers. Participants 55 RR-DTC treated with lenvatinib. Main Outcome Measures Progression-free survival (PFS) and overall survival (OS). Results Lenvatinib was the first-line kinase-inhibitor in 96.4% of subjects. Median follow-up was 48 months. Median PFS and OS were 26 [95% confidence interval (CI) 19.06-32.93] and 70 months (95% CI 36-111.99), respectively. Pretreatment setting: Eastern Cooperative Oncology Group (ECOG) performance status was independently related to PFS [ P <.001; hazard ratio (HR) 18.82; 95% CI 3.65-97.08: score 0-1 as reference] and OS (P =.001; HR 6.20; 95% CI 2.11-18.20; score 0-1 as reference); radioactive iodine (RAI) avidity was independently related to PFS (P =.047; HR 3.74; 95% CI 1.01-13.76; avid disease as reference). Patients with good ECOG status (0-1) and RAI-avid disease obtained objective response in 100% of cases and achieved a median PFS of 45 months without any death upon a median follow-up of 81 months. Posttreatment setting: the best radiological response independently predicted PFS (P =.001; HR 4.6; 95% CI 1.89-11.18; partial/complete response as reference) and OS (P =.013; HR 2.94; 95% CI 1.25-6.89; partial/complete response as reference). Conclusion RR-DTC with good performance status and RAI-avid disease obtains the highest clinical benefit from lenvatinib. After treatment initiation, objective response was the only independent survival predictor. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) is a progressive and incurable neurodegenerative disorder, with an unknown etiology and a multifactorial pathophysiology characterized by protein misfolding, neuroinflammation, and neuronal loss. There are three well-discussed main hypotheses for the pathophysiology of AD, which are related to i) the accumulation of amyloid β (Aβ) protein aggregates in the extracellular space, ii) deposition of hyperphosphorylated tau fragments as neurofibrillary tangles, and iii) dysregulation of hemostasis of some neurotransmitters involved in the disease, such as acetylcholine (ACh) and glutamate. The association of all these factors is responsible for installing oxidative stress and neuroinflammation, which contribute to progressive neuronal death in specific brain regions. More recently, other remarkable pathological characteristics have been described, involving changes in all levels of cellular components, especially in the action and function of protein kinases. These enzymes are crucial for cellular regulation since they play a pivotal role in the phosphorylation of protein substrates by transferring a phosphate group from the ATP molecule to threonine, serine, or tyrosine residues. In more recent studies, some kinases have been especially reported by their role in inflammatory and oxidative processes associated to AD, such as cAMP-dependent protein kinase A (PKA), cyclin-dependent protein kinase 5 (CDK5), glycogen synthase kinase 3β (GSK-3β), and the microtubule affinity regulatory kinases (MARKs). Under homeostatic conditions, protein kinases act as cellular signals, directing physiological responses, but in AD pathogenesis, these enzymes have an exacerbated activity in the brain, justifying the need for a better comprehension of their function and role, and how new kinase inhibitors could lead to innovative drugs. In this context, this brief review aimed to compile the literature data related to the most recent efforts and strategies in Medicinal Chemistry in the discovery of new kinase inhibitors, opening new ways to AD therapeutics.

Abstract The protein kinases DYRK1A and DYRK1B are pivotal regulators of cell cycle progression by promoting cell cycle exit into quiescence. DYRK1B appears to play a more important role in cancer cell quiescence than DYRK1A, as evidenced by its overexpression or copy number variations in human tumour samples. Nonetheless, the stimuli driving DYRK1B upregulation and the potential divergence in expression patterns between DYRK1A and DYRK1B remain largely elusive. In the present study, we scrutinized the regulatory pathways modulating DYRK1B expression relative to DYRK1A in PANC-1 and A549 cancer cell lines across varying conditions. Serum deprivation, pharmacological mTOR inhibition and increased cell density resulted in the differential upregulation of DYRK1B compared to DYRK1A. We then aimed to assess the role of protein kinases MST1 and MST2, which are key transmitters of cell density dependent effects. Unexpectedly, exposure to the MST1/2 inhibitor XMU-MP-1 resulted in increased DYRK1B levels in A549 cells. Further investigation into the off-target effects of XMU-MP-1 unveiled the inhibition of Aurora kinases (AURKA and AURKB) as a potential causative factor. Consistently, AURK inhibitors VX-680 (tozasertib), MLN8237 (alisertib), AZD1152-HQPA (barasertib) resulted in the upregulation of DYRK1B expression in A549 cells. In summary, our findings indicate that the expression of DYRK1A and DYRK1B is differentially regulated in cancer cells and reveal that the kinase inhibitor XMU-MP-1 increases DYRK1B expression likely through off target inhibition of Aurora kinases.

BACKGROUND: Multiple studies have confirmed that mitogen-activated protein kinase (MAPK) signaling pathway is involved in cell proliferation, and microRNA (miR) is involved in the occurrence and development of hypertrophic scars. Therefore, the role of miR-27a-3p and MAPK signaling pathways in pathological scar formation has been further explored. OBJECTIVE: To explore the effect of miR-27a-3p on the proliferation of human hypertrophic scar fibroblasts through the MAPK signaling pathway. METHODS: The primary fibroblasts were isolated and collected from the skin samples. The primary fibroblasts were observed by inverted microscope and verified by immunofluorescence. The relative expression level of miR-27a-3p in tissues was detected by qRT-PCR. The target genes of hsa-miR-27a-3p were predicted using the database, and then the predicted target genes were enriched by gene ontology function analysis and biological pathway enrichment analysis of the Kyoto Encyclopedia of Genes and Genomes. There were seven groups: blank control, negative control, miR-27a-3p mimic, miR-27a-3p inhibitor, miR-27a-3p mimic+p38 MAPK inhibitor, miR-27a-3p mimic+extracellular regulated protein kinase inhibitor, miR-27a-3p mimic+c-Jun N-terminal kinase inhibitor. Western blot was used to detect the levels of extracellular regulated protein kinase, c-Jun N-terminal kinase inhibitor. and p38 kinase and their phosphorylation levels. Cell counting kit-8 and EdU were used to detect cell proliferation. RESULTS AND CONCLUSION: Compared with normal skin fibroblasts, hypertrophic scar fibroblasts had stronger proliferative activity (P < 0.05) and faster proliferation level (P < 0.001). Compared with normal skin, miR-27a-3p was highly expressed in hypertrophic scars (P < 0.001). Compared with the negative control group, overexpression of miR-27a-3p could promote cell proliferation activity (P < 0.001) and proliferation levels (P < 0.001). Compared with the negative control group, knockdown of miR-27a-3p could inhibit the proliferation activity (P < 0.05) and proliferation levels (P < 0.001). Compared with the negative control group, overexpression of miR-27a-3p promoted the phosphorylated levels of extracellular regulated protein kinase, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase (P < 0.05). Compared with the negative control group, knockdown of miR-27a-3p inhibited the phosphorylated levels of extracellular regulated protein kinase, c-Jun N-terminal kinase, and p38 MAPK (P < 0.05). Compared with the miR-27a-3p mimic group, specific inhibitors of extracellular regulated protein kinase, c-Jun N-terminal kinase, and p38 MAPK reversed the effects of miR-27a-3p on the proliferative activity (P < 0.01) and proliferation level (P < 0.001) of fibroblasts. To conclude, these results suggest that miR-27a-3p promotes the proliferation of human hypertrophic scar fibroblasts by activating the MAPK signaling pathway. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions Cell cycle inhibition is an established therapeutic approach for some cancers. A multicenter, single‐arm, phase 2 trial (ClinicalTrials.gov identifier NCT00937937) of the cyclin‐dependent kinase inhibitor SCH 727965 (NSC 747135; dinaciclib) was conducted in patients with metastatic melanoma to determine its clinical activity.Patients with metastatic melanoma of cutaneous or mucosal origin were eligible if they had zero to one previous treatments, a Zubrod performance status of 0–1, and adequate organ function. SCH 727965 50 mg/m2 was given intravenously every 3 weeks until progression. Co‐primary end points were 1‐year overall survival (OS) and 6‐month progression‐free survival (PFS).Seventy‐two patients were enrolled from July 1, 2009, to November 1, 2010, at 24 institutions. Sixty‐eight percent of patients had M1c disease, and 43% had elevated lactate dehydrogenase levels. Twenty‐eight patients (39%) experienced grade 4 adverse events, including 20 cases of neutropenia. Sixty‐seven patients were evaluable for response. There was a response in zero of 67 patients (95% confidence interval [CI], 0%–5%), and stable disease was observed in 21%. The estimated median PFS was 1.4 months (95% CI, 1.4–1.5 months), and the 6‐month PFS rate was 6% (2%–13%). The median OS was 8.2 months (95% CI, 5.5–10.5 months), and the 1‐year OS rate was 38% (95% CI, 26%–49%).This multicenter, US National Cancer Institute Cancer Therapy Evaluation Program‐sponsored trial of SCH 727965 was conducted at a time when the current generation of effective therapies for melanoma were not available. Although the null hypothesis of 1‐year OS was rejected, the minimal PFS impact and substantive toxicity indicated that this regimen lacks justification for further investigation as a single agent. [ABSTRACT FROM AUTHOR]