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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]

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]

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]

To report the use of tofacitinib in ten patients with scleritis where the traditional immunomodulation was not successful or could not be used. A retrospective chart review. Tofacitinib was successful in the treatment of scleritis in patients either recalcitrant to or intolerant to conventional therapy in 9 out of 10 cases reported here. Two patients had developed reactivation of herpetic infection after 1 month of starting tofacitinib. The duration from diagnosis of scleritis to the institution of tofacitinib therapy varied from 1 month to 60 months. Duration of follow-up varies from 2 months to 11 months. Tofacitinib can be used as an important future option for managing recurrent and recalcitrant cases of scleritis. [ABSTRACT FROM AUTHOR]

A tyrosine-kinase inhibitor (TKI) is indicated as a first-line treatment for patients with non-small-cell lung cancer (NSCLC) harboring an epidermal growth-factor – receptor (EGFR) mutation. Chemotherapy (ChT) given in combination with an EGFR-TKI in this setting is of interest. We conducted a meta-analysis of phase III randomized trials comparing EGFR-TKI + ChT vs. EGFR-TKI alone as first-line therapy for advanced NSCLC harboring an activating EGFR mutation. Three studies evaluated gefitinib + ChT (NEJ009, GAP-Brain, and Noronha et al.) and another evaluated osimertinib + ChT (FLAURA-2). Those four eligible studies included 1413 patients with non-squamous NSCLCs, 826 (58%) with an exon-19 deletion (ex19del) and 541 (38%) with EGFRL858R. The EGFR-TKI + ChT combination was significantly associated with prolonged PFS (hazard ratio [HR]: 0.52 [95% confidence interval (CI): 0.45–0.59]; p < 0.0001) and OS (HR: 0.69 [0.52–0.93]; p = 0.01). PFS was particularly improved for patients with brain metastases (HR: 0.41[0.33–0.51]; p < 0.00001). For patients with untreated, advanced, EGFR-mutated NSCLCs, the EGFR-TKI + ChT combination, compared to EGFR-TKI alone, was associated with significantly prolonged PFS and OS. However, further studies are needed to identify which patients will benefit the most from the combination. PROSPERO CRD42024508055 [ABSTRACT FROM AUTHOR]

Kinase is an enzyme that helps in the phosphorylation of the targeted molecules and can affect their ability to react with other molecules. So, kinase influences metabolic reactions like cell signaling, secretory processes, transport of molecules, etc. The increased activity of certain kinases may cause various types of cancer, i.e. leukemia, glioblastoma, and neuroblastomas. So, the growth of particular cancer cells can be prevented by the inhibition of the kinase responsible for those cancers. Natural products are the key resources for the development of new drugs where approximately 60% of anti-tumor drugs are being developed with the same including specific kinase dwellers. This study comprised molecular interactions of various molecules (obtained from natural sources) as kinase inhibitors for the treatment of cancer. It is expected that by analyzing the skeleton behavior, the process of action, and the body-related activity of these organic products, new cancer-avoiding molecules can be developed. [ABSTRACT FROM AUTHOR]

Juvenile dermatomyositis (JDM) is a rare autoimmune disease most commonly with proximal weakness due to inflammation and characteristic skin rashes. Most patients have a chronic or polycyclic disease course on standard therapy so better treatments are needed. An interferon signature is well-established in key tissues of JDM. Janus kinase inhibitors (jakinibs), which can decrease IFN signaling, are therefore appealing as a targeted therapy. Herein is a review of the growing literature on JDM patients in jakinibs, including specifics of their jakinib exposure, summary of efficacy, disease features, and characteristics of patients treated, and safety parameters. The vast majority of refractory JDM patients respond to jakinib therapy, though they have varied features, doses, and previous/concurrent medications, and data is largely retrospective. Jakinibs are an exciting and promising treatment in JDM. Evaluation with larger prospective controlled studies is needed to answer remaining questions about jakinibs in JDM regarding dosing, which JDM patients to treat with jakinibs, potential biomarkers to use, and how best to monitor safety risks in JDM. [ABSTRACT FROM AUTHOR]

Non-small-cell lung cancer (NSCLC) is the primary form of lung cancer globally and remains a leading cause of mortality. Anaplastic lymphoma kinase (ALK) mutations, such as I1171N + L1198H, have been discovered to confer resistance to current ALK inhibitors, reducing their therapeutic effectiveness. Addressing drug resistance necessitates exploring selective inhibitors for innovative therapeutic approaches. In this study, a structure-based pharmacophore model, using ALK-approved inhibitors, was developed to screen an In-house database for potential mutant ALK inhibitors. Compounds with requisite pharmacophoric features were evaluated for binding potential against the I1171N + L1198H ALK mutant phenotype. Selected hits underwent assessment for chemical reactivity, and dynamics stability. The study identified five chemical scaffolds (NS1-5) with favorable binding modes and pharmacokinetic properties. The conformational ensembles featured the average RMSD values, ranging from 0.4 to 0.6 nm. RMSF analysis revealed consistent side chain fluctuations with reduced flexibility, while Rog analysis indicated convergence of most complexes. NS1 and NS5, in particular emerged as promising candidates, exhibiting remarkable performance than others, with binding free energies of −210.12 ± 9.94 and −163.68 ± 11.14 kcal/mol, respectively. These findings thus suggest further exploration and optimisation of NS1 and NS5 for mutant ALK inhibitors for the treatment of NSCLC. [ABSTRACT FROM AUTHOR]

We hypothesize that digital droplet polymerase chain reaction (ddPCR) would optimize the treatment strategies in epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) relapsed patients. In this study, we compared the efficacy of third-generation TKIs with various T790M statuses via ddPCR and next-generation sequencing (NGS). NGS was performed on blood samples of patients progressed from previous EGFR-TKIs for resistance mechanism. T790M-negative patients received further liquid biopsy using ddPCR for T790M detection. A cohort of 40 patients were enrolled, with 30.0% (12/40) T790M-positive via NGS (Group A). In another 28 T790M-negative patients by NGS, 11 (39.3%) were T790M-positive (Group B) and 17 (60.7%) were T790M-negative (Group C) via ddPCR. A relatively longer progression-free survival (PFS) was observed in group A (NR) and group B (10.0 months, 95% CI 7.040–12.889) than in group C (7.0 months, 95% CI 0.000–15.219), with no significant difference across all three groups (p = 0.196), or between group B and C (p = 0.412). EGFR-sensitive mutation correlated with inferior PFS (p = 0.041) and ORR (p = 0.326), and a significantly lower DCR (p = 0.033) in T790M-negative patients via NGS (n = 28). This study indicates that ddPCR may contribute as a supplement to NGS in liquid biopsies for T790M detection in EGFR-TKIs relapsed patients and help to optimize the treatment strategies, especially for those without coexistence of EGFR-sensitive mutation. identifier is NCT05458726. [ABSTRACT FROM AUTHOR]

Atopic dermatitis is a prevalent skin condition causing dry, pruritic, inflammatory skin lesions that can result in patient distress. Various emerging classes of therapy, including biologics and Janus kinase inhibitors, have been developed in recent years. A literature search of PubMed was conducted to explore existing literature and clinical trials. Treatment options and adverse effects were summarized by class and severity. JAK inhibitors and biologics are efficacious options for adults with severe atopic dermatitis. Using the Eczema Area and Severity Index (EASI) from 11 randomized control trials, the highest efficacy was seen with upadacitinib 30 mg with 70% of patients achieving EASI-75. Older, immune-inhibiting treatment options are still appropriate options to improve patient conditions. A meta-analysis of 39 randomized control trials concluded high dose cyclosporine is more effective at improving quality of life and itch when compared to azathioprine and methotrexate. Newly developed topical and systemic medications improve disease and itch severity and can be considered in patients without adequate control with their initial treatment regimen. Adverse effects must be considered when using the newer options, although major adverse events were not seen. Current management options are efficacious, but adherence is required for any effect. [ABSTRACT FROM AUTHOR]

In this report, we describe the case of a 28-year-old female with bilateral breast cancer in the setting of a BRCA1 mutation, who presented to dermatology with an eczematous reaction, ultimately diagnosed as a cutaneous immune-related adverse event (cirAE) secondary to an immune checkpoint inhibitor (ICI), pembrolizumab. Our case report highlights a novel therapeutic option for an eczematous cirAE: the topical JAK 1/2 inhibitor, ruxolitinib. CirAEs can occur in up to 55% of patients on ICIs, a class of medications seeing rapidly increasing use in cancer therapy, and prior research has demonstrated that ICI-induced dermatitis may involve different pathways than traditionally observed in their spontaneous counterparts. Specifically, marked Th1 skewing is noted in ICI-induced dermatitis, as opposed to a predominant Th2 response which typically characterizes spontaneous atopic dermatitis. To our knowledge, this is the first case report in the literature discussing use of a topical JAK inhibitor, ruxolitinib, in the treatment of topical steroid-refractory cirAEs. Furthermore, as topical JAK inhibitors are thought to not carry the risks of systemic JAK inhibitors, including malignancy, ruxolitinib cream is a promising therapeutic option for this challenging patient population. [ABSTRACT FROM AUTHOR]

Noninfectious scleritis typically takes a chronic course, and systemic corticosteroids or disease-modifying anti-rheumatic drug (DMARD) treatment may be inevitable for a prolonged period. Janus kinase (JAK) inhibitors are a relatively new therapeutic option for inflammatory diseases, and three cases of successful treatment of scleritis with tofacitinib, a substance targeting JAK-1 and -3, have been published up to now. We here describe the case of a 51-years-old female patient with bilateral anterior and posterior scleritis who, after treatment failure of multiple DMARDs, finally achieved clinical quiescence of disease under treatment with upadacitinib, a selective JAK-1 inhibitor. [ABSTRACT FROM AUTHOR]

This letter reports a case of a 60-year-old Chinese woman with rheumatoid arthritis who experienced a hepatitis B virus (HBV) outbreak after discontinuing treatment with a Janus kinase inhibitor (tofacitinib) and methotrexate. The patient had previously tested negative for HBV and had normal liver function tests during treatment. The abrupt discontinuation of the immunosuppressive medications led to the activation of HBV and severe liver dysfunction. The authors suggest that clinicians should avoid abruptly discontinuing JAK inhibitor therapy to prevent fulminant hepatitis and further research is needed to determine effective corticosteroid dosages for managing withdrawal reactions. [Extracted from the article]

This study aimed to compare the efficacy and safety of different treatment modalities for previously untreated advanced EGFR-mutated non-squamous non-small-cell lung cancer (NSCLC). This retrospective study included 196 advanced EGFR-mutated non-squamous NSCLC. 107 received EGFR-tyrosine kinase inhibitor (EGFR-TKI) monotherapy (T), 53 received EGFR-TKI + bevacizumab (T + A), and 36 received EGFR-TKI + bevacizumab + chemotherapy (T + A + C). The endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and adverse events (AEs). The median PFS was 27 months in the T + A + C group, 17 months in the T + A group, and 10 months in the T group. The multivariate analysis showed lower disease progression in the T + A + C group (HR, 0.377; 95% CI, 0.224–0.634; p <.001). Subgroup analysis showed that the T + A + C group did significantly improve PFS in patients with metastatic organs ≥2, brain metastases, liver metastases, and EGFR 19del compared to T + A group. No significant improvement in OS in the T + A + C group versus the T + A group, but a significant benefit in the subgroup of patients with metastatic organs ≥2. We also performed a subgroup analysis of the T + A + C group versus the T group, which similarly showed that the T + A + C group had better PFS than the T group in most subgroups, and the T + A + C group significantly improved OS in patients with metastatic organ ≥2 and liver metastases compared with the T group. The ORR was significantly higher in the T + A + C group than A + T and T groups (83.3% vs 71.7% vs 60.7%, p =.033). In safety, the T + A + C group had a higher incidence of AEs, but the majority was grade 1–2. The most frequent AEs of grade ≥ 3 were leukopenia (8.3%) and increased aminotransferase (8.3%) in the T + A + C group. First-generation EGFR-TKI plus bevacizumab plus chemotherapy was a promising strategy for advanced EGFR-mutated non-squamous NSCLC. [ABSTRACT FROM AUTHOR]

As part of our continuous efforts to discover novel c-Met inhibitors as antitumor agents, four series of thiazole/thiadiazole carboxamide-derived analogues were designed, synthesised, and evaluated for the in vitro activity against c-Met and four human cancer cell lines. After five cycles of optimisation on structure–activity relationship, compound 51am was found to be the most promising inhibitor in both biochemical and cellular assays. Moreover, 51am exhibited potency against several c-Met mutants. Mechanistically, 51am not only induced cell cycle arrest and apoptosis in MKN-45 cells but also inhibited c-Met phosphorylation in the cell and cell-free systems. It also exhibited a good pharmacokinetic profile in BALB/c mice. Furthermore, the binding mode of 51am with both c-Met and VEGFR-2 provided novel insights for the discovery of selective c-Met inhibitors. Taken together, these results indicate that 51am could be an antitumor candidate meriting further development. [ABSTRACT FROM AUTHOR]

A series of OA-tacrine hybrids with the alkylamine linker was designed, synthesized, and evaluated as effective cholinesterase inhibitors for the treatment of Alzheimer's disease (AD). Biological activity results demonstrated that some hybrids possessed significant inhibitory activities against acetylcholinesterase (AChE). Among them, compounds B4 (hAChE, IC50 = 14.37 ± 1.89 nM; SI > 695.89) and D4 (hAChE, IC50 = 0.18 ± 0.01 nM; SI = 3374.44) showed excellent inhibitory activities and selectivity for AChE as well as low nerve cell toxicity. Furthermore, compounds B4 and D4 exhibited lower hepatotoxicity than tacrine in cell viability, apoptosis, and intracellular ROS production for HepG2 cells. These properties of compounds B4 and D4 suggest that they deserve further investigation as promising agents for the prospective treatment of AD. [ABSTRACT FROM AUTHOR]

The design of kinase inhibitors targeting the oncogenic kinase BCR-ABL constitutes a promising paradigm for treating chronic myeloid leukaemia (CML). Nevertheless, the efficacy of imatinib, the first FDA-approved targeted therapy for CML, is curbed by the emergence of resistance. Herein, we report the identification of the 2-methoxyphenyl ureidobenzothiazole AK-HW-90 (2b) as a potent pan-BCR-ABL inhibitor against imatinib-resistant mutants, particularly T315I. A concise array of six compounds 2a–f was designed based on our previously reported benzothiazole lead AKE-5l to improve its BCR-ABLT315I inhibitory activity. Replacing the 6-oxypicolinamide moiety of AKE-5l with o-methoxyphenyl and changing the propyl spacer with phenyl afforded 2a and AK-HW-90 (2b) with IC50 values of 2.0 and 0.65 nM against BCR-ABLT315I, respectively. AK-HW-90 showed superior anticancer potency to imatinib against multiple cancer cells (NCI), including leukaemia K-562. The obtained outcomes offer AK-HW-90 as a promising candidate for the treatment of CML and other types of cancer. [ABSTRACT FROM AUTHOR]

Bis-thiazole derivatives were synthesised conforming to the Pim1 pharmacophore model following Hantzsch condensation. Pim1 has a major role in regulating the G1/S phase which upon inhibition the cell cycle stops at its early stages. Derivatives 3b and 8b showed the best Pim1 IC50 0.32 and 0.24 µM, respectively relative to staurosporine IC50 0.36 µM. Further confirmation of 3b and 8b Pim1 inhibition was implemented by hindering the T47D cell cycle at G0/G1 and S phases where 3b showed 66.5% cells accumulation at G0/G1 phase while 8b demonstrated 26.5% cells accumulation at the S phase compared to 53.9% and 14.9% of a control group for both phases, respectively. Additional in vivo cytotoxic evaluation of 3b and 8b revealed strong antitumor activity with up-regulation of caspase-3 and down-regulation of VEGF and TNF α immune expression with concomitant elevation of malondialdehyde levels in case of 8b. [ABSTRACT FROM AUTHOR]

New quinoline-pyridine hybrids were designed and synthesised as PIM-1/2 kinase inhibitors. Compounds 5b, 5c, 6e, 13a, 13c, and 14a showed in-vitro low cytotoxicity against normal human lung fibroblast Wi-38 cell line and potent in-vitro anticancer activity against myeloid leukaemia (NFS-60), liver (HepG-2), prostate (PC-3), and colon (Caco-2) cancer cell lines. In addition, 6e, 13a, and 13c significantly induced apoptosis with percentage more than 66%. Moreover, 6e, 13a, and 13c significantly induced caspase 3/7 activation in HepG-2 cell line. Furthermore, 5c, 6e, and 14a showed potent in-vitro PIM-1 kinase inhibitory activity. While, 5b showed potent in-vitro PIM-2 kinase inhibitory activity. Kinetic studies using Lineweaver–Burk double-reciprocal plot indicated that 5b, 5c, 6e, and 14a behaved as competitive inhibitors while 13a behaved as both competitive and non-competitive inhibitor of PIM-1 kinase enzyme. Molecular docking studies indicated that, in-silico affinity came in coherence with the observed in-vitro inhibitory activities against PIM-1/2 kinases. [ABSTRACT FROM AUTHOR]

The pharmacokinetic (PK) and toxicokinetic profile of a drug from its preclinical evaluation helps the researcher determine whether the drug should be tested in humans based on its safety and toxicity. Preclinical studies require time and resources and are prone to error. Moreover, according to the United States Food and Drug Administration Modernisation Act 2, animal testing is no longer mandatory for new drug development, and an animal-free alternative, such as cell-based assay and computer models, can be used. Different physiologically based PK models were developed for an anaplastic lymphoma kinase inhibitor in rats and monkeys after intravenous and oral administration using its physicochemical properties and in vitro characterisation data. The developed model was validated against the in vivo data available in the literature, and the validation results were found within the acceptable limit. A parameter sensitivity analysis was performed to identify the properties of the compound influencing the PK profile. This work demonstrates the application of the physiologically based PK model to predict the PKs of a drug, which will eventually assist in reducing the number of animal studies and save time and cost of drug discovery and development. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is an autoimmune disorder necessitating immunosuppressive therapy. Remarkable progress has been made in the treatment of RA over recent decades, particularly with the development of biological disease-modifying antirheumatic drugs (bDMARDs) and Janus kinase inhibitors (JAKi). Nonetheless, the development of new drugs has been accompanied by concerns regarding the association between these novel therapies and the risk of malignancy. This narrative review aims to discuss the understanding of RA, conventional synthetic (cs) DMARDs, bDMARDs, JAKi, and their association with malignancy. Furthermore, the review discusses the management of malignancy in patients receiving b/tsDMARDs. Although recent studies suggest that the potential risk of malignancy of methotrexate and a JAKi tofacitinib, it is essential to avoid indiscriminate withholding of treatment by those agents, as this may lead functional impairment and increased mortality. Therefore, the adoption of a Treat-to-Target (T2T) approach considering individual patient characteristics, becomes of utmost importance. Rheumatologists should maintain a vigilant stance regarding malignancy in this context, recognizing the importance of early detection and management. Implementing a screening program for malignancies is indispensable, and the use of computed tomography screening may enhance the effectiveness of management strategies. [ABSTRACT FROM AUTHOR]

The p-toluene sulfonic acid (p-TSA) catalyzed cascade ring closing transformation has been executed for the preparation of novel spiroquinazolinone compounds 4 and 5 by the reaction between anthranilamide and cyclohexanone followed by subsequent acylation. These molecules were then examined against the inhibitory activity of Acetylcholineterase (AchE). The tested compounds revealed moderate anti-AChE activity of IC50 values ranging from 46.675 to 14.256 µM). The described results lead toward the development of compounds 4b and 5c having promising anti-AChE activities with IC50 values at the micromolar level. The docking study suggests that these hybrid spiroquinazolinone scaffold might facilitate the further development of investigated compounds as anti-Alzheimer agents. [ABSTRACT FROM AUTHOR]

Serious phosphatidylinositol 3 kinase (PI3K) inhibitor-related pneumonitis has raised clinical concerns, and integrated data for this condition are lacking. Randomized controlled trials (RCTs) comparing PI3K inhibitor therapy with control treatments from electronic databases and registrations were searched from inception to 1 April 20231 April 2023seven1 April 2023. The outcomes of our study were the incidence and risk of all-grade and grade ≥ 3 PI3K inhibitor-associated pneumonitis compared with controls. The meta-analysis included 13 studies comprising 3916 patients. The incidence of all-grade and grade ≥ 3 pneumonitis was 3.7% (82/2210) and 3.0% (35/1162) in patients treated with PI3K inhibitors. PI3K inhibitors significantly increased the risk of all-grade and grade ≥ 3 pneumonitis compared with controls (RR 5.63, 95% CI [2.97, 10.65], P < 0.00001; RR 6.85, 95% CI [2.45, 19.11], P = 0.0002, respectively) with no significant heterogeneity across studies. In terms of different PI3K inhibitors, copanlisib and idelalisib significantly increased the risk of pneumonitis compared to controls (RR 4.99, 95% CI [1.19, 21.01], P = 0.03; RR 5.53, 95% CI [2.35, 13.01], P < 0.0001, respectively). PI3K inhibitors significantly increased the risk of pneumonitis compared with controls, and most cases are severe or even life-threatening. CRD42022318878 [ABSTRACT FROM AUTHOR]

Recent studies have gradually elucidated the pathogenesis of inflammatory bowel disease; thus, the Janus kinase (JAK)-signal transducers and activators of transcription pathway are strongly involved in the pathophysiology of inflammatory bowel disease. Generally, Janus kinase inhibitors are being used for the treatment of rheumatoid arthritis and other immunological diseases, with the therapeutic promising effects. Currently, in Japan, three Janus kinase inhibitors, namely tofacitinib, filgotinib, and upadacitinib, are available for the treatment of patients with active ulcerative colitis. Therefore, evaluating the efficacy and safety of each JAK inhibitor is essential for determining the role of JAK inhibitors in future therapeutic strategies for inflammatory bowel disease (IBD). [ABSTRACT FROM AUTHOR]

Janus kinase inhibitors (JAKis) are a group of drugs with a different mechanism of action from biologics and are most rapidly uptaken in the rheumatology field. JAK is a protein kinase activated in the cytoplasm by multiple cytokines and hormones involved in inflammatory pathology. The expression of JAK has been observed in various diseases, indicating the utility of JAK inhibitors in a wide variety of immune-mediated inflammatory diseases. Clinical trials are underway for a number of different rheumatic diseases based on the therapeutic efficacy of JAKis, which is comparable to that of biologics. This article will review the current status of JAKis for rheumatic diseases in terms of efficacy and safety and extend to future clinical applications for rare diseases. [ABSTRACT FROM AUTHOR]

Janus Kinase inhibitors (JAKi) are a new class of oral therapies for the treatment of moderate-severe ulcerative colitis with additional potential for the treatment of moderate-severe Crohn's disease. In contrast to biologic therapies JAKi provide the opportunity for non-immunogenic once or twice daily oral therapies. Janus Kinase inhibitors for the treatment of ulcerative colitis and Crohn's disease based on mechanism of action, pharmacokinetics, clinical trial and real-world data regarding safety and efficacy; focusing on regulatory approvals in the U.S. and Europe. Janus Kinase inhibitors are considered among the 'advanced therapies' for IBD and are approved for the treatment of moderate to severe ulcerative colitis in adults with pending approvals for Crohn's disease in the U.S. JAKi offer non-immunogenic, oral options for patient not responding to other conventional agents but, have been 'restricted' by the FDA to patients with inadequate response to TNF blockers. JAKi offer rapidly acting oral alternatives to biologic agents for moderate-severe ulcerative colitis where the risks of cardiovascular and thrombotic events noted in rheumatoid arthritis have not been observed in IBD clinical trials. Nevertheless, monitoring of infections (primarily herpes zoster) and risk factors for cardiovascular and thrombotic complications is appropriate. [ABSTRACT FROM AUTHOR]

Biliary tract carcinoma (BTC) is a heterogenous group of aggressive hepatic malignancies, second to hepatocellular carcinoma per prevalence. Despite clinical research advancement, the overall 5-year survival rate is just above 2%. With the identification of somatic core mutations in half of cholangiocarcinomas. In the intrahepatic subtype (iCCA), it is possible to target mutational pathways of pharmacological interest. Major attention has been drawn to fibroblast growth factor receptor (FGFR), especially the type 2 (FGFR2), found mutated in 10–15% of iCCAs. FGFR2 fusions became the target of novel tyrosine-kinase inhibitors investigated in clinical studies, showing promising results so as to gain regulatory approval by American and European committees in recent years. Such drugs demonstrated a better impact on the quality of life compared to standard chemotherapy; however, side effects including hyperphosphatemia, gastrointestinal, eye, and nail disorders are common although mostly manageable. As FGFR inhibitors may soon become the new alternative to standard chemotherapy in FGFR-mutated cholangiocarcinoma, accurate molecular testing and monitoring of acquired resistance mechanisms will be essential. The possible application of FGFR inhibitors in first-line treatment, as well as in combination with current standard treatments, remains the next step to be taken. [ABSTRACT FROM AUTHOR]

Alopecia areata is a heterogenous, immune-mediated hair loss disorder that can affect any hair-bearing site on the body. Despite being one of the most prevalent autoimmune skin diseases, treatments have historically been limited to off-label medications that have demonstrated limited efficacy, especially in more severe forms of disease. Thus, there has long been an unmet need for rigorously studied therapeutics in alopecia areata. Janus kinase inhibitors have proven to be an effective class of drugs for treating several inflammatory disorders. One such drug, baricitinib, has recently demonstrated significant hair regrowth in phase 2 and 3 alopecia areata trials. It has since become the first systemic therapy approved for treating severe alopecia areata. This review examines the role of Janus kinase pathways in alopecia areata's pathogenesis and the safety and efficacy of baricitinib for treating severe alopecia areata. The approval of baricitinib for treating severe alopecia areata marks a major milestone in the disease's history. While baricitinib has proven to be efficacious for this indication and has demonstrated an overall good safety profile, patients' individual risk factors for serious adverse events should be assessed during shared decision-making with patients before initiating treatment. [ABSTRACT FROM AUTHOR]

Encorafenib, a potent BRAF kinase inhibitor undergoes significant metabolism by CYP3A4 (83%) and CYP2C19 (16%) and also a substrate of P-glycoprotein (P-gp). Because of this, encorafenib possesses potential for enzyme-transporter related interactions. Clinically, its drug–drug interactions (DDIs) with CYP3A4 inhibitors (posaconazole, diltiazem) were reported and hence there is a necessity to study DDIs with multiple enzyme inhibitors, inducers, and P-gp inhibitors. USFDA recommended clinical CYP3A4, CYP2C19, P-gp inhibitors, CYP3A4 inducers were selected and prospective DDIs were simulated using physiologically based pharmacokinetic modelling (PBPK). Impact of dose (50 mg vs. 300 mg) and staggering of administrations (0–10 h) on the DDIs were predicted. PBPK models for encorafenib, perpetrators simulated PK parameters within twofold prediction error. Clinically reported DDIs with posaconazole and diltiazem were successfully predicted. CYP2C19 inhibitors did not result in significant DDI whereas strong CYP3A4 inhibitors resulted in DDI ratio up to 4.5. Combining CYP3A4, CYP2C19 inhibitors yielded DDI equivalent CYP3A4 alone. Strong CYP3A4 inducers yielded DDI ratio up to 0.3 and no impact of P-gp inhibitors on DDIs was observed. The DDIs were not impacted by dose and staggering of administration. Overall, this work indicated significance of PBPK modelling for evaluating clinical DDIs with enzymes, transporters and interplay. [ABSTRACT FROM AUTHOR]

Encorafenib, a potent BRAF kinase inhibitor gets significantly metabolised by CYP3A4 (83%) and CYP2C19 (16%) and is a substrate for P-glycoprotein (P-gp). Due to significant metabolism by CYP3A4, encorafenib exposure can increase in hepatic and renal impairment and may lead to altered magnitude of drug-drug interactions (DDI). Hence, it is necessary to assess the exposures & DDI's in impaired population. Physiologically based pharmacokinetic modelling (PBPK) was utilised to determine the exposures of encorafenib in hepatic and renal impairment along with altered DDI's. Prospective DDI's were predicted with USFDA recommended clinical CYP3A4, CYP2C19, P-gp inhibitors and CYP3A4 inducers. PBPK models for encorafenib, perpetrators simulated PK parameters within 2-folds error. Encorafenib exposures significantly increased in hepatic as compared to renal impairment because of reduced CYP3A4 levels. Hepatic impairment caused changes in inhibition and induction DDI's, when compared to healthy population. Renal impairment did not cause significant changes in DDIs except for itraconazole. P-gp, CYP2C19 inhibitors did not result in altered DDI's. The DDI's were found to have insignificant correlation with relative exposure increase of perpetrators in case of impairment. Overall, this work signifies use of PBPK modelling for DDI's evaluations in hepatic and renal impairment populations. [ABSTRACT FROM AUTHOR]

Ataxia-Telangiectasia Mutated kinase (ATM kinase) is a well-established protein, maintains genome integrity and modulates cellular responses to DNA breakage. It is acknowledged as a master regulator of Double-Strand Breaks (DSB) and redox sensor. In a variety of human malignancies, cells exhibit resistance to radiation and chemotherapeutic approach and thus, the suppression of ATM kinase is a promising strategy to promote cellular sensitivity. Several Miliusa plants are used for traditional medication and reveal appreciable cytotoxicity against tumours. The objective of this study is to achieve sensitization to resistant cells by identifying potent bioactive inhibitors which can block the activity of ATM kinase. Hence, we considered 14 phytoconstituents from genus Miliusa. In this study, we performed Absorption, Distribution, Metabolism, Excretion, Toxicity (ADMET), drug-likeliness prediction, molecular docking and Molecular Dynamics Simulation (MDS). The docking results were evaluated based on free energy binding (ΔG) and it revealed that conocarpan, epicatechin, rhamnazin and rhamnetin found to be potent inhibitors of ATM kinase. The MD simulation results showed the detailed structure and residue level changes upon binding with novel inhibitors. The present investigation proposes, rhamnazin as an efficient inhibitor owing to significant interaction with ATM kinase by exhibiting better binding energy of −29.72 kJ/mol than standard KU-55933 with −17.76 kJ/mol. [ABSTRACT FROM AUTHOR]

Tuning and assimilation of endoplasmic reticulum (ER) content in each cell of the human body is an essential part of organismal homeostasis and adaptation to stress. As such, the lysosomal turnover of ER (reticulophagy) needs to be regulated in a spatio-temporal as well as cell-type specific manner. We recently identified CSNK2/CK2 (casein kinase 2) as the enzyme that phosphorylates the reticulophagy receptors RETREG1/FAM134B and RETREG3/FAM134C and regulates their activity. Phosphorylation of the receptors is a prerequisite for their subsequent functional ubiquitination and the formation of high-density clusters, presumably representing active macroautophagy/autophagy sites at the ER membrane. Consistently, treatment with kinase inhibitor SGC-CK2-1, knockdown of endogenous CSNK2, or mutation of respective phospho-sites prevents ubiquitination, the formation of high-density clusters as well as reticulophagy flux. We hypothesize that CSNK2 has a broader impact on ER and Golgi content in a cell-type and context-specific manner by orchestrating the activity of several autophagy receptors and potentially also factors of the ER-associated protein degradation pathway. [ABSTRACT FROM AUTHOR]

Baricitinib is an oral selective Janus kinase 1/2 inhibitor approved for moderate-to-severe atopic dermatitis (AD) in adults. To evaluate absolute Eczema Area and Severity Index (EASI) and SCORing of Atopic Dermatitis (SCORAD) outcomes over 16 weeks and to link disease severity categories to quality of life (QoL) improvements. This post-hoc analysis included patients enrolled in Phase3 monotherapy (BREEZE-AD1/AD2) and topical corticosteroid (TCS) combination therapy (BREEZE-AD7) trials and analyzed baricitinib 2 and 4 mg vs. placebo. Categorical outcomes were analyzed using Fisher's exact test. Significantly more baricitinib-treated patients reached EASI ≤ 7 and SCORAD < 25 as early as week 1 in monotherapy and week 2 in TCS combination therapy, compared to placebo. Significant response vs. placebo was sustained until week 16 for EASI ≤ 7 (AD1/2 [p-value vs. placebo]: 2 mg = 19.9%, 4 mg = 25.4% [p = 0.001] and AD7: 2 mg = 40.4% [p = 0.087], 4 mg = 48.6% [p = 0.003]) and SCORAD < 25 (AD1/2: 2 mg = 12.2%, 4 mg = 19.4% [p = 0.001] and AD7: 2 mg = 30.3% [p = 0.025], 4 mg = 34.2% [p = 0.004]) severity categories. These effects were accompanied by rapid improvements in QoL. Baricitinib-treated patients rapidly achieved recommended absolute EASI and SCORAD treatment outcomes which were sustained until week 16. Improvements in QoL were greater than EASI severity categories reflected, indicating that physician-assessed scores do not necessarily correlate with patients' impression of AD severity. [ABSTRACT FROM AUTHOR]

Traditionally, epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) has been regarded as a cold tumor based on the immunosuppressive tumor immune microenvironment (TIME). However, recent studies have found that EGFR-tyrosine kinase inhibitor (EGFR-TKI) treatment could shift host immunity from immunosuppressive to immunosupportive TIME, which has renewed hopes of immunotherapy. In this review, we highlight five main immunotherapy-based therapies for patients after EGFR-TKI failure, including safety and efficacy data from prospective and retrospective clinical studies. The efficacy of immunotherapy alone is extremely limited. Immunotherapy plus chemotherapy show an ORR of 29.5%–59.3% and an mPFS of about 7 months. There is still scarce evidence for immunotherapy plus antiangiogenesis therapy. A combination of immunotherapy with EGFR-TKIs exhibits higher treatment-related adverse events and lower clinical outcomes compared to EGFR-TKI alone. Importantly, immunotherapy plus antiangiogenesis and chemotherapy achieves an mPFS of 6.9–10.2 months. In general, the strategy of combining immunotherapy with chemotherapy and/or an antiangiogenic drug is a novel and promising method for treating advanced NSCLC after EGFR-TKI failure. Therefore, the dominant population of EGFR-TKI resistant patients were characterized by EGFR uncommon mutation, EGFR L858R mutation, PD-L1 ≥ 50%, prior antiangiogenic drugs, and negative T790 M mutation for immunotherapy-based therapy. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is an inflammatory disease affecting over 20% of the pediatric population, with 85% of cases presenting before the age of five. Recently, therapeutic options in pediatric patients have evolved rapidly, following extensive development in adult treatments. This review will encompass relevant molecular drivers, along with an overlook on treatment modalities in pediatric AD, as well as a summary of pipeline treatments in clinical trials for pediatric patients from PubMed, Google Scholar, and Clinicaltrials.gov up to July 2022. Topical corticosteroids are the mainstay for AD flares in adults and children. Topical approved agents in pediatric AD are calcineurin inhibitors, crisaborolecrisaborole, and ruxolitinib. Dupilumab is the only FDA approved biologic for patients with AD from six months of age. A Janus kinase inhibitor, upadacitinib, is a systemic treatment approved for pediatric AD patients (age >12 years). Systemic immunosuppressants used in pediatric AD include methotrexate, azathioprine, cyclosporinecyclosporine, and mycophenolate mofetil. Data regarding disease prevention are conflicting, however, an abundance of research has transpired regarding amelioration of symptoms and induction of disease clearance by targeting numerous pathological mechanisms. Understanding the pediatric AD phenotype will further advance the field and the development of improved therapeutics. [ABSTRACT FROM AUTHOR]

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. Imatinib mesylate revolutionized the management of advanced/metastatic GIST, and remains the standard first-line therapy in this setting. Upon development of secondary resistance, sunitinib and regorafenib are used as subsequent treatments, although clinical benefit is often non-durable. Ripretinib is a type II kinase inhibitor targeting KIT and PDGFRA mutations and resistance through switching active I and inactive II forms. This drug profile article provides an overview of the current state of the art treatment algorithm for advanced/metastatic GIST, focusing on the role of ripretinib in the fourth-line setting as defined by currently available clinical trials evidence. The mechanism of action, the safety profile, efficacy, and clinical application of ripretinib are presented. In addition, the Phase I study (NCT02571036) through which the optimal dose was established and the Phase III trials that assessed the efficacy and safety of ripretinib as fourth- (INVICTUS) and second-line treatment (INTRIGUE) are presented. Ripretinib is a safe and an effective therapy for the fourth-line setting in advanced/metastatic GIST. Future studies should evaluate combination schedules and the identification of markers predictive of benefit from ripretinib. [ABSTRACT FROM AUTHOR]

Glycogen synthase kinase 3β (GSK-3β) catalyses the hyperphosphorylation of tau protein in the Alzheimer's disease (AD) pathology. A series of novel thieno[3,2-c]pyrazol-3-amine derivatives were designed and synthesised and evaluated as potential GSK-3β inhibitors by structure-guided drug rational design approach. The thieno[3,2-c]pyrazol-3-amine derivative 16b was identified as a potent GSK-3β inhibitor with an IC50 of 3.1 nM in vitro and showed accepted kinase selectivity. In cell levels, 16b showed no toxicity on the viability of SH-SY5Y cells at the concentration up to 50 µM and targeted GSK-3β with the increased phosphorylated GSK-3β at Ser9. Western blot analysis indicated that 16b decreased the phosphorylated tau at Ser396 in a dose-dependent way. Moreover, 16b effectively increased expressions of β-catenin as well as the GAP43, N-myc, and MAP-2, and promoted the differentiated neuronal neurite outgrowth. Therefore, the thieno[3,2-c]pyrazol-3-amine derivative 16b could serve as a promising GSK-3β inhibitor for the treatment of AD. [ABSTRACT FROM AUTHOR]

Identification of highly selective type II kinase inhibitors is described. Two different chiral peptidomimetic scaffolds were introduced on the tail region of non-selective type II kinase inhibitor GNF-7 to enhance the selectivity. Kinome-wide selectivity profiling analysis showed that type II kinase inhibitor 7a potently inhibited Lck kinase with great selectivity (IC50 of 23.0 nM). It was found that 7a and its derivatives possessed high selectivity for Lck over even structurally conserved all Src family kinases. We also observed that 7a inhibited Lck activation in Jurkat T cells. Moreover, 7a was found to alleviate clinical symptoms in DSS-induced colitis mice. This study provides a novel insight into the design of selective type II kinase inhibitors by adopting chiral peptidomimetic moieties on the tail region. [ABSTRACT FROM AUTHOR]

In the current work, a hybridisation strategy was adopted between the privileged building blocks, benzofuran and piperazine, with the aim of designing novel CDK2 type II inhibitors. The hybrid structures were linked to different aromatic semicarbazide, thiosemicarbazide, or acylhydrazone tails to anchor the designed inhibitors onto the CDK2 kinase domain. The designed compounds showed promising CDK2 inhibitory activity. Compounds 9h, 11d, 11e and 13c showed potent inhibitory activity (IC50 of 40.91, 41.70, 46.88, and 52.63 nM, respectively) compared to staurosporine (IC50 of 56.76 nM). Moreover, benzofurans 9e, 9h, 11d, and 13b showed promising antiproliferative activities towards different cancer cell lines, and non-significant cytotoxicity on normal lung fibroblasts MRC-5 cell line. Furthermore, a cell cycle analysis as well as Annexin V-FITC apoptosis assay on Panc-1 cell line were performed. Molecular docking simulations were performed to explore the ability of target benzofurans to adopt the common binding pattern of CDK2 type II inhibitors. [ABSTRACT FROM AUTHOR]

High levels of Wee1 expression have been seen in a variety of malignancies, including breast cancer, cervical cancer and leukaemia. Due to the positive link between cancer and Wee1 expression, the protein has become a particularly relevant therapeutic target in the fight against cancer. The current study aimed to identify potential Wee1 kinase inhibitors from FDA-approved drugs using in silico approach. The drug candidates were virtually screened in silico against Wee1 kinase using molecular docking. The binding free energy of the nine top-scoring compounds was determined, after which its bioactivity was predicted by three well-validated QSAR models. The molecular dynamics of FDA-approved drugs dasatinib and cangrelor with Wee1 kinase were studied for 100 ns. The results demonstrated that the top-scoring compounds identified as potential Wee1 inhibitors exhibited favourable binding energies (docking scores), and its stability with Wee1 was evident by the binding free energy calculation. The result of the AutoQSAR ensemble/consensus prediction showed that this set of compounds had satisfactory inhibitory attributes. The MD simulation showed stable complexes throughout the duration of the simulation. Based on the data obtained from this study, we recommend the top-scoring compounds for further preclinical investigation for its potential to inhibit Wee1 kinase in cancer. [ABSTRACT FROM AUTHOR]

A series of novel tetrahydropyrimidin-4-yl)pyridine derivatives 6(a–h) have been designed and synthesized as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The chemical structures of all newly synthesized compounds were characterized by spectroscopic methods (IR, 1H NMR, 13C NMR) and elemental analyzes. The in vitro studies showed that all the synthesized derivatives showed significant BChE inhibitory activity more potent than donepezil as the standard (IC50 values less than 0.1 µM). All the target compounds demonstrated good AChE inhibitory effects comparable with donepezil as the reference drug with IC50 values ranging from 0.08 to 0.1 µM. The best results were obtained by 4-methyl substituted derivative 6d with IC50 value of 0.082 µM which was comparable with AChE inhibitory effects of donepezil (IC50 = 0.079 µM). [ABSTRACT FROM AUTHOR]

To address potential safety concerns of Janus Kinase Inhibitors (JAK-Is), we characterized their safety profile in the atopic dermatitis (AD) patient population. In this retrospective observational study, we used propensity score-based methods and a Poisson modeling framework to estimate the incidence of health outcomes of interest (HOI) for the AD patient. To that end, two mutually exclusive cohorts were created using a real world data resource: a rheumatoid arthritis (RA) cohort, where we directly quantify the safety risk of JAK-Is on HOIs, and an AD cohort, that comprises the target population of interest and to whom we transport the results obtained from the RA cohort. The RA cohort included all adults who filled at least one prescription for a JAK-I (tofacitinib, baricitinib, or upadacitinib) between 1 January 2017 and 31 January 2020. The AD cohort consisted of all adults diagnosed with AD during the same period. We first estimated the incidence rate of each HOI in the RA cohort, and then transported the results to the AD population. The RA and AD cohorts included 5,296 and 261,855 patients, respectively. On average, patients in the AD cohort were younger, more often male, more likely to be Asian, and had higher household income. They also had a lower prevalence of several comorbid conditions including hypertension, chronic kidney disease, obesity, and depression. Overall, the transported incidence rates of the HOIs to the AD cohort were lower than those obtained in the RA cohort by 13–50%. We applied transportability methods to characterize the risk of the HOIs in the AD population and found absolute risks higher than that of the general population. Future work is needed to validate these conclusions in comparable populations. [ABSTRACT FROM AUTHOR]

1,3-Bis-3-(4-chlorophenyl)-2,3-dihydroquinazolin-4(1H)-on-2-thioxopropane (C), a quinazoline derivative was synthesized and well-characterized in order to evaluate its potential to act as VEGFR-2 and Aurora kinase inhibitor. 1H NMR, elemental analysis and FT-IR confirmed the structure of the synthesized compound (C). Since, VEGFR-2 plays a crucial role in angiogenesis, it is hence a significant pharmaceutical target for the development of anti-angiogenic agents. While on the other hand, AURKA is an enzyme that is believed to induce normal cell proliferation and is encoded with over-expression witnessed in various types of malignant cancers. The electrostatic potential and the molecular geometry of the conformers 1-3, was demonstrated by DFT calculations. The results of which, revealed that the syn conformer 3 was the most stable. The molecular docking studies gave a brief insight about the binding of the conformer 3, also suggesting its potential to act as dual inhibitor, that inhibits VEGFR-2 and Aurora kinase, thereby could play an important role in cancer inhibition. [ABSTRACT FROM AUTHOR]

Arginine kinase from Trypanosoma cruzi (TcAK) catalyzes the interconversion of arginine and phosphoarginine to maintain the ATP/ADP cell balance, and is involved in the parasites' energetic homeostasis and stress responses. Using virtual screening approaches, some plant-derived polyphenolic pigments, such as anthocyanidins, were predicted to inhibit TcAK activity. Here, it was demonstrated that the anthocyanidin delphinidin showed a non-competitive inhibition mechanism of TcAK (Ki arginine = 1.32 µM and Ki ATP = 500 µM). Molecular docking simulations predicted that delphinidin occupies part of the ATP/ADP pocket, more specifically the one that binds the ribose phosphate, and molecular dynamics simulations confirmed the amino acids involved in binding. Delphinidin exerted trypanocidal activity over T. cruzi trypomastigotes with a calculated IC50 of 19.51 µM. Anthocyanidins are low-toxicity natural products which can be exploited for the development of trypanocidal drugs with less secondary effects than those currently used for the treatment of Chagas disease. [ABSTRACT FROM AUTHOR]

Introduction: Itch is a distressing atopic dermatitis (AD) symptom that impacts quality of life. With the emergence of multiple new agents for the treatment of AD, the ability and speed with which an agent reduces itch may factor in agent selection. Objective: In this study, the primary objective was to quantify the rate at which agents for AD provide itch reduction using the peak itch numerical rating scale (NRS) data from phase II and III clinical trials. Methods: A PubMed literature search was performed in February 2020 to find phase II and III randomized clinical trials for the treatment of AD published from 2014 to 2020. A TIMEACLIR-Itch value was calculated from NRS data to represent the time to meaningful itch reduction. Results: We find a shorter TIme to achieving a MEAningful CLInical Response for itch reduction (TIMEACLIR-Itch) for small molecule inhibitors when compared to biologic agents. We also observe that nemolizumab achieves TIMEACLIR-Itch more quickly than IL-4 or IL-4/13 agents. Conclusion: These findings support the role that IL-31 has in producing itch and the role Janus kinase inhibitors (JAKinibs) play in itch reduction. This comparison of TIMEACLIR-Itch for different treatments may help guide therapy and management for AD patients. [ABSTRACT FROM AUTHOR]

In recent decades, Rheumatoid arthritis (RA) treatment landscape has evolved with the induction of new biological and targeted therapies that provide significant therapeutic benefits in patients with sustained disease. Tumor necrosis factor inhibitors (TNFi) were the first biologics used in the treatment of RA. Although they present a significant efficacy, an insufficient response of some patients led to further research and discovery of targeted therapies, such as Janus kinase inhibitors (JAKi), which act at a molecular level, regulating many cytokines. Clinical benefits have been seen with both TNFi and JAKi as monotherapy and combined with conventional synthetic disease-modifying antirheumatic drugs. Still, some significant side effects have been reported with JAKi, and several questions remain about their safety and selectivity in action. This review summarizes the current knowledge on the mechanism of action, the clinical efficacy, and safety of TNFi vs. JAKi. TNFi and JAKi are particularly useful in treating inflammatory arthropathies. Both drug categories are recommended by ACR and EULAR institutions in RA patients suffering from moderate to severe disease. Safety data in long-term studies are required to determine the optimal benefit to the risk profile of JAKi use. [ABSTRACT FROM AUTHOR]