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Background Objective Animals Materials and Methods Results Conclusions and Clinical Relevance Janus kinase inhibitors (JAKi) have been shown to reduce pruritus and improve associated inflammatory skin lesions in canine atopic dermatitis (cAD).To evaluate the efficacy and safety of ilunocitinib, in comparison to oclacitinib, for the control of cAD in a randomised, blinded trial.Three‐hundred‐and‐thirty‐eight dogs with cAD.Dogs were randomised to receive oclacitinib (0.4–0.6 mg/kg twice daily for 14 days; then once daily) or ilunocitinib (0.6–0.8 mg/kg once daily), for up to 112 days. Owners assessed pruritus using an enhanced Visual Analog Scale (PVAS). Investigators assessed skin lesions using the Canine Atopic Dermatitis Extent and Severity Index, 4th interaction (CADESI‐04).Reduction in pruritus and CADESI‐04 scores was similar for both treatment groups from Day (D)0–D14. PVAS scores increased between D14 and D28 for oclacitinib and decreased for ilunocitinib. On D28 to D112, mean PVAS and CADESI‐04 scores were significantly lower for ilunocitinib compared to oclacitinib (p ≤ 0.003 and p ≤ 0.023, respectively). On D28 to D112, a greater number of ilunocitinib‐treated dogs achieved clinical remission of pruritus (i.e. PVAS score <2). Subjective assessment of overall response was significantly better for ilunocitinib on D28 to D112 (p ≤ 0.002). Both drugs demonstrated similar safety throughout the study.Ilunocitinib rapidly and safely controlled signs of cAD. Ilunocitinib demonstrated significantly better control of pruritus and skin lesions compared to oclacitinib, with more dogs achieving clinical remission of pruritus. [ABSTRACT FROM AUTHOR]

Protein kinases are key regulators of numerous biological processes and aberrant kinase activity can cause various diseases, particularly cancer. Herein, we report the identification of new series of highly selective kinase inhibitors based on the thieno[3,2‐b]pyridine scaffold. The weak interaction of the thieno[3,2‐b]pyridine core with the kinase hinge region allows for profoundly different binding modes all of which maintain high kinome‐wide selectivity, as illustrated by the isomers MU1464 and MU1668. Thus, this core structure provides a template of ATP‐competitive but not ATP‐mimetic inhibitors that are anchored at the kinase back pocket. Mapping the chemical space around the central thieno[3,2‐b]pyridine pharmacophore afforded highly selective inhibitors of the kinase Haspin, exemplified by the compound MU1920 that fulfils criteria for a quality chemical probe and is suitable for use in in vivo applications. However, despite the role of Haspin in mitosis, the inhibition of Haspin alone was not sufficient to elicit cytotoxic effect in cancer cells. The thieno[3,2‐b]pyridine scaffold can be used in a broader context, as a basis of inhibitors targeting other underexplored protein kinases, such as CDKLs. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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). Results: 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%). Conclusions: 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. A multicenter, US National Cancer Institute Cancer Therapy Evaluation Program‐sponsored, 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. Dinaciclib failed to demonstrate sufficient clinical activity to justify its further investigation as a single agent. [ABSTRACT FROM AUTHOR]

A comprehensive study on the physicochemical properties of gem‐fluorinated O‐heterocyclic substituents is reported. Systematic additive effects of introducing O‐ and gem‐CF2 group introduction on acidic properties (pKa) of the corresponding carboxylic acids/protonated primary amines were demonstrated. The impact of the O/CF2 moieties on lipophilicity (LogP) was found to be complex; significant mutual influence of the corresponding polar moieties governed the compound's overall properties in this case. Biological evaluation of MAPK kinase inhibitors incorporating the title substituents demonstrated their utility as promising fragments for bioisosteric replacements in drug discovery campaigns. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction Methods Results Conclusion First‐line osimertinib is widely used to treat patients with epidermal growth factor receptor (EGFR)‐mutated non‐small cell lung cancers (NSCLC). In clinical practice, rechallenge therapy with another EGFR‐tyrosine kinase inhibitor (TKI) is often performed after first‐line TKI discontinuation owing to resistance or toxicity; however, the efficacy and toxicity of EGFR‐TKI rechallenge after first‐line osimertinib have not been adequately investigated. This study aimed to examine the efficacy and safety of EGFR‐TKI rechallenge with another TKI.This multicenter prospective observational study enrolled patients with EGFR‐mutated NSCLC who received first‐line osimertinib and another EGFR‐TKI as second‐ or third‐line treatment between September 2018 and August 2020.Fifty‐three patients received rechallenge with another EGFR‐TKI in the second‐line (n = 38, 71.7%) or third‐line (n = 15, 28.3%) setting. The primary reason for first‐line osimertinib discontinuation was toxicity in 32 (60.4%, 17 patients with pneumonitis) and disease progression in 20 (37.7%) patients. The most common rechallenge EGFR‐TKI was afatinib (n = 24, 45.3%), followed by gefitinib (n = 16, 30.2%) and erlotinib (n = 8, 15.1%). The real‐world time to treatment failure (rwTTF) was 7.3 months. The rwTTF for the toxicity discontinuation and progressive disease discontinuation groups was 9.3 months and 5.1 months, respectively, (HR 1.61, p = 0.119). EGFR‐TKI rechallenge was discontinued due to toxicity in nine patients (17.0%), but no patient developed pneumonitis.EGFR‐TKI rechallenge with another TKI is well tolerated in patients with EGFR‐mutated NSCLC. Thus, it may be a useful treatment option after first‐line osimertinib failure, especially after osimertinib discontinuation due to toxicity. [ABSTRACT FROM AUTHOR]

Objective: Eczema is the most burdensome skin condition worldwide and topical anti‐inflammatory treatments are commonly used to control symptoms. The relative effectiveness and safety of different topical anti‐inflammatory treatments is uncertain. Design: Network meta‐analysis performed within a Cochrane systematic review to compare and statistically rank efficacy and safety of topical anti‐inflammatory eczema treatments. Data Sources: Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase and trial registries to June 2023. Eligibility Criteria for Selected Trials: Included trials were within‐participant or between‐participant randomised controlled trials. Participants had eczema that was not clinically infected and was not contact dermatitis, seborrheic eczema or hand eczema. Interventions were topical anti‐inflammatory treatments but not complementary treatments, antibiotics alone, wet wraps, phototherapy or systemic treatments. Comparators were no treatment/vehicle or another topical anti‐inflammatory. Results: We identified 291 trials (45,846 participants), mainly in high‐income countries. Most were industry‐funded with median 3 weeks treatment duration. Risk of bias assessed using the Cochrane Risk of Bias 2.0 tool was high in 89% of trials, mainly due to risk of selective reporting. Network meta‐analysis of binary outcomes ranked potent and/or very potent topical steroids, tacrolimus 0.1% and ruxolitinib 1.5% among the most effective treatments for improving patient‐reported symptoms (40 trials, all low confidence) and clinician‐reported signs (32 trials, all moderate confidence). For investigator global assessment, the Janus kinas inhibitors ruxolitinib 1.5%, delgocitinib 0.5% or 0.25%, very potent/potent topical steroids and tacrolimus 0.1% were ranked as most effective (140 trials, all moderate confidence). Continuous outcome data were mixed. Local application site reactions were most common with tacrolimus 0.1% (moderate confidence) and crisaborole 2% (high confidence) and least common with topical steroids (moderate confidence). Skin thinning was not increased with short‐term use of any topical steroid potency (low confidence) but skin thinning was reported in 6/2044 (0.3%) participants treated with longer‐term (6–60 months) topical steroids. Conclusion: Potent topical steroids, Janus kinase inhibitors and tacrolimus 0.1% were consistently ranked as among the most effective topical anti‐inflammatory treatments for eczema. [ABSTRACT FROM AUTHOR]

Infantile bullous pemphigoid (BP) is a rare autoantibody‐mediated skin disorder. We report the effective treatment of a 6‐month‐old infant with BP using baricitinib, a Janus kinase (JAK) inhibitor, after failure with steroids and intravenous immunoglobulin. The patient achieved full remission and discontinued all medications without any relapses. To our knowledge, this is the first case of baricitinib used in an infant with BP. [ABSTRACT FROM AUTHOR]

MEN1703 is a first‐in‐class, oral, Type I dual PIM/FMS‐like tyrosine kinase 3 inhibitor (FLT3i) investigated in a Phase I/II DIAMOND‐01 trial in patients with acute myeloid leukaemia (AML). Gilteritinib is a highly potent and selective oral FLT3i approved for the treatment of relapsed/refractory AML with FLT3 mutations. Although gilteritinib showed strong single‐agent activity in FLT3‐mutated AML, the development of gilteritinib resistance limits response durability, indicating the importance of novel combination strategies to improve disease outcome. PIM kinases govern FLT3‐ITD signalling and increased PIM kinase expression is found in samples from AML patients relapsing on FLT3i. Here, we report that the simultaneous inhibition of PIM and FLT3, through the combination of MEN1703 and gilteritinib, can consistently improve the in vitro/in vivo antitumor activity over the single agents, demonstrating the benefit of this combination. Moreover, we demonstrate that resistance to gilteritinib can be circumvented by combining MEN1703 with gilteritinib. MEN1703 interferes with FLT3 upregulation, Mcl‐1 overexpression and PIM kinase signalling, which are all involved in FLT3i resistance. We also show that MEN1703 downregulates stromal cytokines that promote cytokine‐mediated resistance of AML blast cells to FLT3 inhibition. These results demonstrate the importance of the combination approach to overcome microenvironment‐mediated resistance to FLT3 inhibitors. [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]

ABSTRACT Various studies have reported resistance mechanisms and treatment methods after epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitor treatment; however, treatment policies have not yet been established, and few cases have reported transformation to pleomorphic carcinoma (PC) as the resistance mechanism. Herein, we report the case of a 66‐year‐old woman who was diagnosed with Stage 4A lung adenocarcinoma (cT2bN0M1b) through bronchoscopic biopsy. Genetic profiling revealed an EGFR L858R mutation; therefore, osimertinib was administered as the first‐line therapy and achieved a partial response. After 46 months of osimertinib treatment, the metastases remained under control; however, the primary tumor enlarged and was therefore resected. Pathological examination confirmed the diagnosis of PC. Genetic testing of the surgical pathology specimen showed that the EGFR mutation L858R was retained, and the patient was considered drug‐resistant owing to the histologic transformation to PC. The patient continued osimertinib therapy and had no recurrence at 9 months postoperatively. Transformation to PC following osimertinib administration is rare, and we report this unique case. This study was approved by the Jichi Medical University Saitama Medical Center Ethics Committee (S24‐073), and written informed consent was obtained from the patient. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Aim Methods Results Conclusions Three Janus kinase (JAK) inhibitors are approved for ulcerative colitis (UC) in Japan.To compare the real‐world efficacy and safety of these three JAK inhibitors in UC.This was a multicentre, retrospective study of patients with UC started on JAK inhibitors. The primary outcome was clinical remission at 10, 26 and 58 weeks, and at the most recent follow‐up. To compare the efficacy and safety among the JAK inhibitors, we created three matched cohorts (upadacitinib vs. filgotinib, tofacitinib vs. filgotinib and upadacitinib vs. tofacitinib) using propensity score matching.We identified 228 upadacitinib‐treated patients (median follow‐up 49 weeks; IQR 25–72), 215 filgotinib‐treated patients (follow‐up 56 weeks; IQR 17–82) and 159 tofacitinib‐treated patients (follow‐up 112 weeks; IQR 10–258). Clinical remission rates for upadacitinib, filgotinib and tofacitinib at the most recent follow‐up were 72.8%, 50.6% and 45.8%, respectively. Over 70% of the patients previously treated with other biologics or JAK inhibitors achieved clinical remission with upadacitinib. On multivariate analysis, the number of previous advanced therapies was inversely associated with the efficacy of filgotinib and tofacitinib. Comparative analysis showed that upadacitinib‐treated patients had higher efficacy and lower risk of discontinuation than patients treated with other JAK inhibitors. However, upadacitinib had a significant risk of acne.Considering the particularly high efficacy of upadacitinib, even in patients with refractory UC, filgotinib or tofacitinib may be considered as an upfront JAK inhibitor before using upadacitinib. [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]

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]

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]

Janus kinase inhibitors (JAKi) are drugs that block tyrosine kinases responsible for transducing cytokine signals. The first JAKi was approved by the US Food and Drug Administration (FDA) in 2011 to treat rheumatoid arthritis in adults. A pediatric indication was not approved until 8 years later, for acute graft‐versus‐host disease. Since then, topical and oral formulations have gained FDA approval for pediatric patients with dermatologic diseases. While increasing evidence supports the safety of these medications in adults, data are limited in children. We sought to determine whether JAKi adverse events (AEs) as reported in clinical trials and via postapproval pharmacovigilance services are comparable in adult and pediatric patients. Pharmacovigilance data were extracted from the FDA's Adverse Event Reporting System and the Canada Vigilance Adverse Reaction Online Database for baricitinib, upadacitinib, abrocitinib, ruxolitinib, and tofacitinib. The pooled data were analyzed to detect the most common AEs for specific JAKi and for the drug class. We assessed 399,649 AEs from 133,216 adults and 2883 AEs from 955 patients under 18 years old and identified slightly different AE profiles for the two age groups. Both populations had increased risk for infections and gastrointestinal AEs. However, pediatric patients reported a higher proportion of blood and lymphatic disorders, while reports of nervous system and musculoskeletal/connective tissue disorders were more common in adults. The spectrum of AEs extracted from pharmacovigilance reports was similar to clinical trials. The JAKi AE profiles we observed may prove helpful in counseling patients and their parents before starting therapy and for monitoring once patients are on therapy. [ABSTRACT FROM AUTHOR]

Aim: The objective of this study was to compare the clinical effectiveness of baricitinib and abatacept in patients with rheumatoid arthritis (RA). Methods: This study included 274 patients treated with abatacept and 241 treated with baricitinib who were followed for >52 weeks. Potential treatment selection bias was addressed by using inverse probability of treatment weighting. The paired t‐test was used to assess differences in Clinical Disease Activity Index (CDAI) score relative to baseline. A generalized estimating equation was used to compare the two treatment groups. Results: The estimated mean CDAI score was 18.2 at baseline and significantly decreased to 12.6 at 4 weeks, 8.9 at 12 weeks, 7.4 at 24 weeks, and 6.1 at 52 weeks in the abatacept group. The estimated mean CDAI score was 18.6 at baseline and significantly decreased to 9.5 at 4 weeks, 6.5 at 12 weeks, 5.7 at 24 weeks, and 5.5 at 52 weeks in the baricitinib group. The baricitinib group had significantly lower CDAI scores at 4, 12, and 24 weeks compared to the abatacept group. Subgroup analyses revealed that this difference was evident among patients with high disease activity and without concomitant use of methotrexate but was less pronounced among those with remission to moderate disease activity status with methotrexate use. Conclusion: Both baricitinib and abatacept were effective in reducing disease activity in patients with RA. Baricitinib demonstrated potential advantages over abatacept in terms of early disease control, particularly in patients with high disease activity and without methotrexate use. [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]

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]

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]

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]

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]

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]

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]

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]

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]

In this study, we synthesized a variety of indole derivatives using commercially available 2,5‐dimethoxybenzaldehyde 18 as a starting material. The synthetic route involves a sequential usage of Knoevenagel and Fischer indolization reactions as key steps and the Fischer indolization is facilitated by deep eutectic solvent (DES) such as L‐tartaric acid/dimethylurea (TA:DMU). All the compounds prepared here are characterized by HRMS, 1H‐NMR and 13C‐NMR data. The methodology described in this study showcases the utility of deep eutectic solvents in facilitating the synthesis of diverse indole derivatives, thereby expanding the toolkit of sustainable synthetic methodologies. These compounds are medicinally important and play a key role as an effective template in Kinase inhibitors (CK2). Various functionalized indeno[1,2‐b]indole scaffolds synthesized here might be valuable as novel inhibitors of human CK2. Elevated levels of protein kinase CK2, previously known as casein kinase 2 or II, have been linked to higher cell growth and proliferation in both normal and cancerous cells. [ABSTRACT FROM AUTHOR]

There is an urgent need to fully understand the biology of third generation EGFR‐tyrosine kinase inhibitors (EGFR‐TKIs), particularly osimertinib, and to develop mechanism‐driven strategies to manage their acquired resistance. Transient receptor potential melastatin‐2 (TRPM2) functions as an important regulator of Ca2+ influx, but its role in mediating therapeutic efficacies of EGFR‐TKIs and acquired resistance to EGFR‐TKIs has been rarely studied. This study has demonstrated a previously undiscovered role of suppression of TRPM2 and subsequent inhibition of Ca2+ influx and induction of ROS and DNA damage in mediating apoptosis induction and the therapeutic efficacy of osimertinib against EGFR mutant NSCLC. The rebound elevation represents a key mechanism accounting for the emergence of acquired resistance to osimertinib and other third generation EGFR‐TKIs. Accordingly, targeting TRPM2 is a potentially promising strategy for overcoming and preventing acquired resistance to osimertinib, warranting further study in this direction including the development of cancer therapy‐optimized TRPM2 inhibitors. [ABSTRACT FROM AUTHOR]

Background: Building on our prior work that RNA alternative splicing modulates the druggability of kinase fusions, this study probes the clinical significance of sole reciprocal fusions. These rare genomic arrangements, despite lacking kinase domains at the DNA level, demonstrated potential RNA‐level druggability in sporadic cases from our prior research. Methods: Utilizing the large‐scale multicenter approach, we performed RNA sequencing and clinical follow‐up to evaluate a broad spectrum of kinase fusions, including ALK, ROS1, RET, BRAF, NTRK, MET, NRG1, and EGFR, in 1943 patients. Results: Our findings revealed 51 instances (2.57%) of sole reciprocal fusions, predominantly in lung (57%), colorectal (14%), and glioma (10%) cancers. Comparative analysis with an MSKCC cohort confirmed the prevalence in diverse cancer types and identified unique fusion partners and chromosomal locales. Cross‐validation through RNA‐NGS and FISH authenticated the existence of functional kinase domains in subsets including ALK, ROS1, RET, and BRAF, which correlated with positive clinical responses to targeted kinase inhibitors (KIs). Conversely, fusions involving EGFR, NRG1, and NTRK1/2/3 generated nonfunctional transcripts, suggesting the need for alternative therapeutic interventions. Conclusion: This inaugural multicenter study introduces a novel algorithm for detecting and treating sole reciprocal fusions in advanced cancers, expanding the patient population potentially amenable to KIs. [ABSTRACT FROM AUTHOR]

Efficacy and safety of ritlecitinib (an oral JAK3/TEC family kinase inhibitor) were evaluated in patients with nonsegmental vitiligo (NSV) across Fitzpatrick skin types (FSTs). Patients with FST I‐III ('light skin'; n = 247) and FST IV‐VI ('dark skin'; n = 117) received once‐daily ritlecitinib 50 mg (with/without 4‐week loading dose), low‐dose ritlecitinib or placebo for 24 weeks. At baseline, patients with light skin displayed higher CLM‐1 and NCR1 serum levels than patients with dark skin (p < 0.05). At 24 weeks, ritlecitinib 50 mg improved the extent of depigmentation measured by percent change from baseline in facial‐vitiligo area scoring index (placebo‐adjusted mean difference [90% CI]) in patients with light (−15.2 [−24.7, −5.8]; p = 0.004) and dark (−37.4 [−50.3, −24.4]; p < 0.0001) skin, with continuous re‐pigmentation through week 48. Treatment‐emergent adverse events were similar across FSTs. At weeks 4 and 24, ritlecitinib 50 mg reduced CXCL11 serum levels (p < 0.001) in patients with light skin, whereas patients with dark skin had increased levels at week 4 (p = 0.05) and no significant change at week 24. Ritlecitinib 50 mg decreased IL‐9 and IL‐22 expression levels in dark skin compared with light skin (qPCR; p < 0.05). These differences in immune dysregulations may explain why NSV patients with dark skin respond to therapy earlier than patients with light skin. [ABSTRACT FROM AUTHOR]

Small molecular kinase inhibitors play a key role in modern cancer therapy. Protein kinases are essential mediators in the growth and progression of cancerous tumors, rendering involved kinases an increasingly important target for therapy. However, kinase inhibitors are almost insoluble in water because of their hydrophobic aromatic nature, often lowering their availability and pharmacological efficacy. Direct drug functionalization with polar groups represents a simple strategy to improve the drug solubility, availability, and performance. Here, we present a strategy to functionalize secondary amines with oligoethylene glycol (OEG) phosphate using a one‐pot synthesis in three exemplary kinase inhibiting drugs Ceritinib, Crizotinib, and Palbociclib. These OEG‐prodrug conjugates demonstrate superior solubility in water compared to the native drugs, with the solubility increasing up to 190‐fold. The kinase inhibition potential is only slightly decreased for the conjugates compared to the native drugs. We further show pH dependent hydrolysis of the OEG‐prodrugs which releases the native drug. We observe a slow release at pH 3, while the conjugates remain stable over 96 h under physiological conditions (pH 7.4). Using confocal microscopy, we verify improved cell uptake of the drug‐OEG conjugates into the cytoplasm of HeLa cells, further supporting our universal solubility approach. [ABSTRACT FROM AUTHOR]

Background: Alopecia areata (AA) is an autoimmune hair loss disorder characterised by collapse of hair follicle immune privilege and mediated by autoreactive CD8+ T lymphocytes and natural killer cells. Treatment is often unsatisfactory. The Janus kinase‐signal transducer and activator of transcription (JAK–STAT) pathway is implicated in the pathogenesis of AA and Janus Kinase inhibitor (JAKi) medications are promising emerging treatments for AA. Objectives: We evaluated the safety and effectiveness of tofacitinib in a real‐world setting over 18 months of treatment. Methods: A retrospective cohort study of all patients with scalp AA commenced on tofacitinib between 1 November 2016 and 31 May 2019. The primary endpoint was the percent change in Severity of Alopecia Tool (SALT) score at 18 months. Results: Two hundred and two patients were included. After 18 months of treatment, 55.9%, 42.6% and 29.2% achieved 50%, 75% and 90% reductions in their SALT scores respectively. Increased duration of AA was a negative predictor of hair regrowth. Males and patients with baseline SALT ≥90 were slower to respond to treatment in the first 12 months. One hundred and twenty‐four patients and 168 patients received concomitant systemic corticosteroids or low‐dose oral minoxidil during tofacitinib therapy respectively. There were no serious adverse events. Conclusion: Tofacitinib was a safe and effective treatment for patients with moderate‐to‐severe AA. Further randomised controlled studies are needed to establish the optimal treatment regimen. [ABSTRACT FROM AUTHOR]

Kinases, a class of enzymes controlling various substrates phosphorylation, are pivotal in both physiological and pathological processes. Although their conserved ATP binding pockets pose challenges for achieving selectivity, this feature offers opportunities for drug repositioning of kinase inhibitors (KIs). This study presents a cost‐effective in silico prediction of KIs drug repositioning via analyzing cross‐docking results. We established the KIs database (278 unique KIs, 1834 bioactivity data points) and kinases database (357 kinase structures categorized by the DFG motif) for carrying out cross‐docking. Comparative analysis of the docking scores and reported experimental bioactivity revealed that the Atypical, TK, and TKL superfamilies are suitable for drug repositioning. Among these kinase superfamilies, Olverematinib, Lapatinib, and Abemaciclib displayed enzymatic activity in our focused AKT‐PI3K‐mTOR pathway with IC50 values of 3.3, 3.2 and 5.8 μM. Further cell assays showed IC50 values of 0.2, 1.2 and 0.6 μM in tumor cells. The consistent result between prediction and validation demonstrated that repositioning KIs via in silico method is feasible. [ABSTRACT FROM AUTHOR]

Long‐term treatment of nonresectable tenosynovial giant cell tumor with pexidartinib is feasible and provides long‐term control and symptomatic improvement, with acceptable tolerance. Treatment interruption is possible, and one half of patients remain without progression after interruption. Among those who relapse, pexidartinib is again active, although not all patients need to resume treatment. [ABSTRACT FROM AUTHOR]

RIPK1 plays a key role in necroptosis and is associated with various inflammatory diseases. Using structure‐based virtual screening, a novel hit with 5‐(1‐benzyl‐1H‐imidazol‐4‐yl)‐1,2,4‐oxadiazole scaffold was identified as an RIPK1 inhibitor with an IC50 value of 1.3 μM. Further structure–activity relationship study was performed based on similarity research and biological evaluation. The molecular dynamics simulation of compound 2 with RIPK1 indicated that it may act as a type II kinase inhibitor. This study provides a highly efficient way to discover novel scaffold RIPK1 inhibitors for further development. [ABSTRACT FROM AUTHOR]

Vitiligo is a chronic skin condition caused by an autoimmune response that results in the progressive loss of melanocytes and recent studies have suggested that Janus kinase inhibitors (JAKi) are emerging as a promising new treatment modality. Therefore, to assess and understand the extent of knowledge in the emerging field of JAKi use in vitiligo, a scoping review of the literature was undertaken. The reviewed articles explored a wide variety of JAKi administered either orally or topically for vitiligo. There were no injectable JAKi studied. Tofacitinib was the most commonly studied oral JAKi in 16 of the 35 studies selected for review, followed by baricitinib (n = 3), and one study each with ritlecitinib, ruxolitinib, and upadacitinib. Ruxolitinib (n = 6) and tofacitinib (n = 6) were the most often studied topical JAKi, followed by delgocitinib (n = 1). Potential benefits may vary between JAKi based on their receptor selectivity profile and coexistent autoimmune diseases. A topical JAKi would be advantageous in limited body area involvement and in adolescents. Concurrent use of JAKi with phototherapy or sun exposure appears beneficial. Most studies permitted the use of other topical agents. Acne‐related events, though frequent yet mild, were reported with both oral and topical JAKi. Nasopharyngitis, upper respiratory tract infections, and headaches were the most common adverse effects seen in the larger trials with JAKi. No serious or clinically meaningful hematology or thromboembolic events were detected. Treatment of vitiligo with oral or topical JAKi seems to be promising and the growing evidence shows a favorable risk‐benefit profile. [ABSTRACT FROM AUTHOR]

Mevalonate kinase is a key regulator of the mevalonate pathway, subject to feedback inhibition by the downstream metabolite farnesyl pyrophosphate. In this study, we validated the hypothesis that monophosphonate compounds mimicking farnesyl pyrophosphate can inhibit mevalonate kinase. Exploring compounds originally synthesized as allosteric inhibitors of farnesyl pyrophosphate synthase, we discovered mevalonate kinase inhibitors with nanomolar activity. Kinetic characterization of the two most potent inhibitors demonstrated Ki values of 3.1 and 22 nm. Structural comparison suggested features of these inhibitors likely responsible for their potency. Our findings introduce the first class of nanomolar inhibitors of human mevalonate kinase, opening avenues for future research. These compounds might prove useful as molecular tools to study mevalonate pathway regulation and evaluate mevalonate kinase as a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Drugs that block DNA replication prevent cell proliferation, which may result in anticancer activity. The latter is dependent on the drug's mode of action as well as on cell type‐dependent responses to treatment. The inhibition of Cell division cycle 7‐related protein kinase (CDC7), a key regulator of DNA replication, decreases the efficiency of origin firing and hampers the restarting of paused replication forks. Here, we show that upon prolonged CDC7 inhibition, breast‐derived MCF10A cells progressively withdraw from the cell cycle and enter a reversible senescent‐like state. This is characterised by the rewiring of the transcriptional programme with the induction of cytokine and chemokine expression and correlates with the accumulation of Cyclic GMP‐AMP synthase (cGAS)‐positive micronuclei. Importantly, cell fate depends on Cellular tumour antigen p53 (p53) function as cells no longer enter senescence but are funnelled into apoptosis upon p53 knockout. This work uncovers key features of the secondary response to CDC7 inhibitors, which could aid the development of these compounds as anticancer drugs. [ABSTRACT FROM AUTHOR]

The mitogen‐activated protein kinase (MAPK) extracellular signal‐regulated kinase 5 (ERK5) is emerging as a promising target in cancer. Indeed, alterations of the MEK5/ERK5 pathway are present in many types of cancer, including melanoma. One of the key events in MAPK signalling is MAPK nuclear translocation and its subsequent regulation of gene expression. Likewise, the effects of ERK5 in supporting cancer cell proliferation have been linked to its nuclear localization. Despite many processes regulating ERK5 nuclear translocation having been determined, the nuclear transporters involved have not yet been identified. Here, we investigated the role of importin subunit alpha (α importin) and importin subunit beta‐1 (importin β1) in ERK5 nuclear shuttling to identify additional targets for cancer treatment. Either importin β1 knockdown or the α/β1 importin inhibitor ivermectin reduced the nuclear amount of overexpressed and endogenous ERK5 in HEK293T and A375 melanoma cells, respectively. These results were confirmed in single‐molecule microscopy in HeLa cells. Moreover, immunofluorescence analysis showed that ivermectin impairs epidermal growth factor (EGF)‐induced ERK5 nuclear shuttling in HeLa cells. Both co‐immunoprecipitation experiments and proximity ligation assay provided evidence that ERK5 and importin β1 interact and that this interaction is further induced by EGF administration and prevented by ivermectin treatment. The combination of ivermectin and the ERK5 inhibitor AX15836 synergistically reduced cell viability and colony formation ability in A375 and HeLa cells and was more effective than single treatments in preventing the growth of A375 and HeLa spheroids. The increased reduction of cell viability upon the same combination was also observed in patient‐derived metastatic melanoma cells. The combination of ivermectin and ERK5 inhibitors other than AX15836 provided similar effects on cell viability. The identification of importin β1 as the nuclear transporter of ERK5 may be exploited for additional ERK5‐inhibiting strategies for cancer therapy. [ABSTRACT FROM AUTHOR]

Epidermal melanin unit integrity is crucial for skin homeostasis and pigmentation. Epidermal growth factor (EGF) receptor (EGFR) is a pivotal player in cell growth, wound healing, and maintaining skin homeostasis. However, its influence on skin pigmentation is relatively unexplored. This study investigates the impact and underlying mechanisms of EGFR inhibitors on skin pigmentation. We evaluated EGF and EGFR expression in various skin cells using quantitative real‐time PCR, Western blot, and immunofluorescence. EGF and EGFR were predominantly expressed in epidermal keratinocytes, and treatment with the EGFR tyrosine kinase inhibitors (EGFR‐TKIs) gefitinib and PD153035 significantly increased stem cell factor (SCF) and endothelin‐1 (ET‐1) expression in cultured keratinocytes. Enhanced melanocyte migration and proliferation were observed in co‐culture, as evidenced by time‐lapse live imaging and single‐cell tracking assays. Furthermore, topical application of gefitinib to guinea pig dorsal skin induced increased pigmentation and demonstrated efficacy in mitigating rhododendrol‐induced leukoderma. Suppression of EGF signaling indirectly enhanced skin pigmentation by upregulating SCF and ET‐1 in epidermal keratinocytes. This novel mechanism highlights the pivotal role of EGF signaling in regulating skin pigmentation, and topical EGFR‐TKI therapy at an appropriate dose may be a promising approach for depigmentation disorder management. [ABSTRACT FROM AUTHOR]

Interleukin‐6 (IL‐6), a pleiotropic cytokine, plays a pivotal role in the pathophysiology of various diseases including diabetes, atherosclerosis, Alzheimer's disease, multiple myeloma, rheumatoid arthritis, and prostate cancer. The signaling pathways associated with IL‐6 offer promising targets for therapeutic interventions in inflammatory diseases and IL‐6‐dependent tumors. Although certain anti‐IL‐6 monoclonal antibodies are currently employed clinically, their usage is hampered by drawbacks such as high cost and potential immunogenicity, limiting their application. Thus, the imperative arises to develop novel small non‐peptide molecules acting as IL‐6 inhibitors. Various natural products derived from diverse sources have been investigated for their potential to inhibit IL‐6 activity. Nevertheless, these natural products remain inadequately explored in terms of their structure‐activity relationships. In response, our review aims to provide syntheses and structure activity perspective of natural IL‐6 inhibitors. The comprehensive amalgamation of information presented in this review holds the potential to serve as a foundation for forthcoming research endeavors by medicinal chemists, facilitating the design of innovative IL‐6 inhibitors to address the complexities of inflammatory diseases. HIGHLIGHTS: Interleukin‐6 (IL‐6), a pleiotropic cytokine, plays a pivotal role in various diseases such as diabetes, atherosclerosis, Alzheimer's disease, multiple myeloma, rheumatoid arthritis, and prostate cancer. This has spurred the development of several clinical valuable drugs, while the IL‐6 signaling pathway continues to attract attention in the field of drug discovery and development.Madindolines (A and B), exemplar natural inhibitors of IL‐6, have demonstrated sub‐micromolar IC50 values in IL‐6‐dependent MH60 cell lines.This review encompasses the total and formal synthesis of madindolines (A and B), explores structure‐activity relationships, and delves into the biological implications of these compounds.Furthermore, the IL‐6 inhibitory potential of natural products exhibiting diverse chemotypes is thoroughly examined.The insights presented herein intend to ignite novel approaches for pioneering IL‐6 inhibitors by synergizing acquired knowledge and computational methodologies and serve as a driving force for expanded explorations into novel IL‐6 inhibitors, propelling a wave of future investigations. [ABSTRACT FROM AUTHOR]

Objective: We combined claims and electronic health record (EHR) data to provide contemporary and accurate estimates of latent tuberculosis (TB) screening among new users of a biologic or targeted synthetic disease‐modifying antirheumatic drug (b/tsDMARD) and assess potential gaps in testing by drug type, patient characteristics, and practice. Methods: Our denominator population was patients in the Rheumatology Informatics System for Effectiveness (RISE) registry and Medicare using a b/tsDMARD in 2018 without a claim or prescription in the year prior. TB screening was assessed in both Medicare and RISE 1 and 3 years before the medication start date. We calculated the proportion screened overall, by medication class, and by practice. We tested for demographic differences in screening using logistic regression. Results: In the year before drug starts, 65.6% of patients had any TB screening; in a 3‐year window, 72.9% had any TB screening. Rates of screening within 1 year by drug type were greater or equal to the overall screening rate for most drugs except for JAK inhibitors (JAKis) (46%) and interleukin‐17 inhibitors (IL‐17is) (11.5%). A lower proportion of Hispanic and Asian patients were screened compared with White patients. Practice screening rates ranged from 20.0% to 92.9% of patients within 1 year. Conclusion: We report higher screening rates than have previously been published because of combining claims and EHR data. However, important safety gaps remain, namely, reduced screening among new users of a JAKi or IL‐17i and among Asian and Hispanic patients, as well as low‐performing practices. Educational initiatives, team‐based care delivery, task shifting, and technological interventions to address observed gaps in patient safety procedures are needed. [ABSTRACT FROM AUTHOR]

Background. Atopic dermatitis control tool (ADCT) is a patient‐reported measure to assess disease control of atopic dermatitis (AD), consisting of the severity of symptoms, itch duration, bother, sleep, daily activities, and mood/emotions. Objectives. We evaluated the alterations of total and individual ADCT item scores during treatment with Janus kinase 1 inhibitor upadacitinib in AD patients. Methods. Forty‐seven patients aged ≥12 years with moderate‐to‐severe AD were treated with oral upadacitinib 15 mg/day plus topical corticosteroids. Total and individual ADCT item scores, eczema area, and severity index (EASI) and peak pruritus numerical rating scale (PP‐NRS) were evaluated. Results. Before treatment, total ADCT correlated with EASI and PP‐NRS. The median percent reduction at months 1, 3, and 6 of upadacitinib treatment was 80%, 76.2%, and 67.4% in total ADCT, 75.28%, 85.06%, and 81.73% in EASI, 66.67%, 75%, and 75% in PP‐NRS, respectively, and percent reduction of total ADCT correlated with that of EASI and PP‐NRS except for no correlations with that of EASI at month 1. The percent reduction of ADCT no.4 was the highest among the 6 items. Conclusions. These results suggest that changes in ADCT reflect the therapeutic effects of upadacitinib and that ADCT can be a treatment target for upadacitinib therapy. Upadacitinib might preferentially improve sleep disturbance. [ABSTRACT FROM AUTHOR]

Introduction: A neurotrophic tropomyosin receptor kinase (NTRK)‐tyrosine kinase inhibitor (TKI) has shown dramatic efficacy against malignant tumors harboring an NTRK fusion gene. However, almost all tumors eventually acquire resistance to NTRK‐TKIs. Method: To investigate the mechanism of resistance to NTRK‐TKIs, we established cells resistant to three types of NTRK‐TKIs (larotrectinib, entrectinib, and selitrectinib) using KM12 colon cancer cells with a TPM3‐NTRK1 rearrangement. Result: Overexpression of 3‐hydroxy‐3‐methylglutaryl‐CoA synthase 2 (HMGCS2) was observed in three resistant cells (KM12‐LR, KM12‐ER, and KM12‐SR) by microarray analysis. Lower expression of sterol regulatory element‐binding protein 2 (SREBP2) and peroxisome proliferator activated receptor α (PPARα) was found in two cells (KM12‐ER and KM12‐SR) in which HMGCS2 was overexpressed compared to the parental KM12 and KM12‐LR cells. In resistant cells, knockdown of HMGCS2 using small interfering RNA improved the sensitivity to NTRK‐TKI. Further treatment with mevalonolactone after HMGCS2 knockdown reintroduced the NTRK‐TKI resistance. In addition, simvastatin and silibinin had a synergistic effect with NTRK‐TKIs in resistant cells, and delayed tolerance was observed after sustained exposure to clinical concentrations of NTRK‐TKI and simvastatin in KM12 cells. In xenograft mouse models, combination treatment with entrectinib and simvastatin reduced resistant tumor growth compared with entrectinib alone. Conclusion: These results suggest that HMGCS2 overexpression induces resistance to NTRK‐TKIs via the mevalonate pathway in colon cancer cells. Statin inhibition of the mevalonate pathway may be useful for overcoming this mechanistic resistance. [ABSTRACT FROM AUTHOR]

The pseudo‐natural product (pseudo‐NP) concept aims to combine NP fragments in arrangements that are not accessible through known biosynthetic pathways. The resulting compounds retain the biological relevance of NPs but are not yet linked to bioactivities and may therefore be best evaluated by unbiased screening methods resulting in the identification of unexpected or unprecedented bioactivities. Herein, various NP fragments are combined with a tricyclic core connectivity via interrupted Fischer indole and indole dearomatization reactions to provide a collection of highly three‐dimensional pseudo‐NPs. Target hypothesis generation by morphological profiling via the cell painting assay guides the identification of an unprecedented chemotype for Aurora kinase inhibition with both its relatively highly 3D structure and its physicochemical properties being very different from known inhibitors. Biochemical and cell biological characterization indicate that the phenotype identified by the cell painting assay corresponds to the inhibition of Aurora kinase B. [ABSTRACT FROM AUTHOR]

This article provides a review of the use of Janus Kinase inhibitors (JAKi) in the treatment of various types of scarring alopecia. It discusses the potential benefits of JAKi therapy in improving symptoms and hair regrowth in patients with conditions such as lichen planopilaris, central centrifugal cicatricial alopecia, folliculitis decalvans, frontal fibrosing alopecia, and dissecting cellulitis of the scalp. The article acknowledges the need for further research to fully understand the effectiveness and potential side effects of JAKi in this context. Overall, JAKi therapy shows promise but more investigation is required. [Extracted from the article]

Key Clinical Message: Generalized lichen planus pigmentosus significantly improved with the daily administration of Tofacitinib at a dosage of 15 mg. [ABSTRACT FROM AUTHOR]

Objectives: EGFR-tyrosine kinase inhibitor (TKI) is used to treat recurrent and metastatic nasopharyngeal carcinoma (rmNPC). This meta-analysis aims to study the efficacy and safety of EGFR-TKI in treating patients with rmNPC. Methods: We conducted a systematic search of PubMed, Embase, and Web of Science up to November 2023, and included literature that met the criteria. We extracted objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), median overall survival (mOS), and adverse reaction-related events and performed meta-analysis using Stata 14.0. Results: A total of nine articles were included. The summary results showed that the ORR for patients treated with EGFR-TKI for rmNPC was 38% (95% CI = 27%-49%), the DCR was 71% (95% CI = 61%-80%), the mPFS was 6.29 months (95% CI = 5.22-7.35), and the mOS was 15.94 months (95% CI = 14.68-17.20). The most common grade 3-4 adverse reaction events in these patients were mucositis, nasopharyngeal necrosis, and oral ulceration. We found an incidence rate of 49% (95% CI = 38%-61%) for grade 3-4 adverse events (AEs). The anti-PD1 combined with TKI treatment method is more effective than the EGFR-TKI alone for treating rmNPC. Conclusion: The study shows that EGFR-TKI has good efficacy in treating rmNPC but does not translate into survival benefits and owns a high incidence of grade 3-4 AEs. More RCT trials are needed in the future to verify the efficacy of anti-PD1 combined with TKI treatment method. [ABSTRACT FROM AUTHOR]

Oncogenic mutations can destabilize signaling proteins, resulting in increased or unregulated activity. Thus, there is considerable interest in mapping the relationship between mutations and the stability of signaling proteins, to better understand the consequences of oncogenic mutations and potentially inform the development of new therapeutics. Here, we develop a tool to study protein‐kinase stability in live mammalian cells and the effects of the HSP90 chaperone system on the stability of these kinases. We determine the expression levels of protein kinases by monitoring the fluorescence of fluorescent proteins fused to those kinases, normalized to that of co‐expressed reference fluorescent proteins. We used this tool to study the dependence of Src‐ and Raf‐family kinases on the HSP90 system. We demonstrate that this sensor reports on destabilization induced by oncogenic mutations in these kinases. We also show that Src‐homology 2 and Src‐homology 3 domains, which are required for autoinhibition of Src‐family kinases, stabilize these kinase domains in the cell. Our expression‐calibrated sensor enables the facile characterization of the effects of mutations and small‐molecule drugs on protein‐kinase stability. [ABSTRACT FROM AUTHOR]

Actinic prurigo is a rare photodermatosis characterized by pruritic papulonodular lesions. Treatment is challenging, especially in children, as sun protection strategies need to be rigorously implemented and symptoms often persist throughout the year. Herein, we present a case of actinic prurigo in an 8‐year‐old patient with rapid and successful relief with baricitinib. [ABSTRACT FROM AUTHOR]