Properties of FDA-approved small molecule protein kinase inhibitors: A 2023 update

Pharmacological Research, Journal Year: 2022, Volume and Issue: 187, P. 106552 - 106552

Published: Nov. 17, 2022

Owing to the dysregulation of protein kinase activity in many diseases including cancer, this enzyme family has become one most important drug targets 21st century. There are 72 FDA-approved therapeutic agents that target about two dozen different kinases and three these drugs were approved 2022. Of drugs, twelve protein-serine/threonine kinases, four directed against dual specificity (MEK1/2), sixteen block nonreceptor protein-tyrosine 40 receptor kinases. The data indicate 62 prescribed for treatment neoplasms (57 solid tumors breast, lung, colon, ten nonsolid such as leukemia, both tumors: acalabrutinib, ibrutinib, imatinib, midostaurin). Four (abrocitinib, baricitinib, tofacitinib, upadacitinib) used inflammatory (atopic dermatitis, psoriatic arthritis, rheumatoid Crohn disease, ulcerative colitis). eighteen multiple diseases. following received FDA approval 2022 specified diseases: abrocitinib dermatitis), futibatinib (cholangiocarcinomas), pacritinib (myelofibrosis). All orally effective with exception netarsudil, temsirolimus, trilaciclib. This review summarizes physicochemical properties all small molecule inhibitors lipophilic efficiency ligand efficiency.

Language: Английский

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Evolving cognition of the JAK-STAT signaling pathway: autoimmune disorders and cancer

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: May 19, 2023

Abstract The Janus kinase (JAK) signal transducer and activator of transcription (JAK-STAT) pathway is an evolutionarily conserved mechanism transmembrane transduction that enables cells to communicate with the exterior environment. Various cytokines, interferons, growth factors, other specific molecules activate JAK-STAT signaling drive a series physiological pathological processes, including proliferation, metabolism, immune response, inflammation, malignancy. Dysregulated related genetic mutations are strongly associated activation cancer progression. Insights into structures functions have led development approval diverse drugs for clinical treatment diseases. Currently, been developed mainly target commonly divided three subtypes: cytokine or receptor antibodies, JAK inhibitors, STAT inhibitors. And novel agents also continue be tested in preclinical studies. effectiveness safety each kind drug warrant further scientific trials before put being applications. Here, we review current understanding fundamental composition function pathway. We discuss advancements JAK-STAT–related pathogenic mechanisms; targeted therapies various diseases, especially disorders, cancers; newly inhibitors; challenges directions field.

Language: Английский

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A Comprehensive Overview of Globally Approved JAK Inhibitors

Pharmaceutics, Journal Year: 2022, Volume and Issue: 14(5), P. 1001 - 1001

Published: May 6, 2022

Janus kinase (JAK) is a family of cytoplasmic non-receptor tyrosine kinases that includes four members, namely JAK1, JAK2, JAK3, and TYK2. The JAKs transduce cytokine signaling through the JAK-STAT pathway, which regulates transcription several genes involved in inflammatory, immune, cancer conditions. Targeting JAK with small-molecule inhibitors has proved to be effective treatment different types diseases. In current review, eleven received approval for clinical use have been discussed. These drugs are abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, upadacitinib. aim review was provide an integrated overview chemical pharmacological data globally approved inhibitors. synthetic routes were described. addition, their inhibitory activities against uses also explained. Moreover, crystal structures summarized, primary focus on binding modes interactions. proposed metabolic pathways metabolites these illustrated. To sum up, could help design new potential therapeutic benefits inflammatory autoimmune

Language: Английский

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CD23 ⁺ IgG1 ⁺ memory B cells are poised to switch to pathogenic IgE production in food allergy

Science Translational Medicine, Journal Year: 2024, Volume and Issue: 16(733)

Published: Feb. 7, 2024

Food allergy is caused by allergen-specific immunoglobulin E (IgE) antibodies, but little known about the B cell memory of persistent IgE responses. Here, we describe, in human pediatric peanut allergy, a population CD23 + IgG1 cells arising type 2 immune responses that contain high-affinity peanut-specific clones and generate IgE-producing upon activation. The frequency correlated with circulating concentrations children allergy. A corresponding “type 2–marked” was identified single-cell RNA sequencing experiments. These differentially expressed interleukin-4 (IL-4)– IL-13–regulated genes, such as FCER2 / , IL4R germline IGHE carried highly mutated receptors (BCRs). In high serum IgE, bind main allergen Ara h mapped to included convergent BCRs across different individuals. Our findings indicate transcribing are unique containing precursors pathogenic likely be involved long-term persistence

Language: Английский

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Janus kinase (JAK) inhibitors in the treatment of neoplastic and inflammatory disorders

Pharmacological Research, Journal Year: 2022, Volume and Issue: 183, P. 106362 - 106362

Published: July 22, 2022

Language: Английский

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Therapeutic Targeting of the Janus Kinase/Signal Transducer and Activator of Transcription Pathway in Cutaneous T-Cell Lymphoma

Cancers, Journal Year: 2025, Volume and Issue: 17(4), P. 568 - 568

Published: Feb. 7, 2025

Background/Objectives: Cutaneous T-cell lymphoma (CTCL) is a rare group of non-Hodgkin lymphomas characterized by the clonal expansion malignant T cells. While current treatments can alleviate symptoms and significant progress has been made in treating leukemic CTCL, definitive cure remains elusive. Dysregulation Janus kinase/signal transducer activator transcription (JAK/STAT) signaling pathway key driver CTCL pathogenesis. As result, therapeutic strategies targeting JAK/STAT have gained momentum, with increasing use JAK inhibitors other agents that effectively suppress this pathway. These immune-modulating therapies broad effects on physiological processes, inflammation, pathological changes associated both inflammatory diseases cancers. Several inhibitors, originally FDA-approved for conditions, are now being investigated cancer treatment. Methods: In paper, brief review literature dysregulation provided, highlighting clinical preclinical studies involving target Results: Specifically, we focus six currently under investigation-golidocitinib, ruxolitinib, cerdulatinib, tofacitinib, upadacitinib, abrocitinib. Additionally, discuss explore mechanisms underlying inhibition CTCL. Furthermore, reported cases which relapsed or emerged following inhibitor Conclusions: Collectively, these findings support potential utility However, further research needed to evaluate safety risks, minimize adverse effects, optimize strategies.

Language: Английский

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Efficacy and Safety of JAK1 Inhibitor Abrocitinib in Atopic Dermatitis

Pharmaceutics, Journal Year: 2023, Volume and Issue: 15(2), P. 385 - 385

Published: Jan. 23, 2023

Abrocitinib is a JAK1 selective inhibitor recently approved for the treatment of moderate-to-severe atopic dermatitis in adults. It has demonstrated efficacy and safety several clinical trials, both children adults, monotherapy, compared with dupilumab. The expected EASI-75 response rate estimates at week 12 are 62.9% (95% CrI 42.5–79.9%) abrocitinib 200 mg 43.0% 24.8–64.0%) 100 mg. shown faster effect than dupilumab as regards early alleviation itch. Because incomplete target selectivity JAK inhibitors, when considered, laboratory screening necessary, latent tuberculosis must be screened for, active infections contraindication, special caution exerted treating elderly patients those predisposed to thromboembolic events. Even though recent meta-analyses trials have not that dermatitis, or its inhibitors dupilumab, modify risk deep venous thrombosis pulmonary embolism, long-term follow-up studies will better define profile abrocitinib.

Language: Английский

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New drug approvals for 2022: Synthesis and clinical applications

Medicinal Research Reviews, Journal Year: 2023, Volume and Issue: 43(6), P. 2352 - 2391

Published: May 21, 2023

Abstract The U.S. Food and Drug Administration has approved a total of 37 new drugs in 2022, which are composed 20 chemical entities 17 biologics. In particular, entities, including small molecule drugs, 1 radiotherapy, 2 diagnostic agents, provide privileged scaffolds, breakthrough clinical benefits, mechanism action for the discovery more potent candidates. structure‐based drug development with clear targets fragment‐based scaffolds have always been important modules field discovery, could easily bypass patent protection bring about improved biological activity. Therefore, we summarized relevant valuable information application, action, synthesis newly 2022. We hope this timely comprehensive review creative elegant inspiration on synthetic methodologies novel extended indications.

Language: Английский

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Visible-Light-Induced Highly Site-Selective Direct C–H Phosphorylation of Pyrrolo[2,3-d]pyrimidine Derivatives with H-Phosphine Oxides

The Journal of Organic Chemistry, Journal Year: 2024, Volume and Issue: 89(5), P. 2996 - 3009

Published: Feb. 15, 2024

An efficient and highly regioselective C6-phosphorylation protocol for pyrrolo[2,3-d]pyrimidine (7-DAP) derivatives with various H-phosphine oxides induced by visible light at room temperature is described the first time. This has been successfully achieved combination of Na2-eosin Y as a photocatalyst LPO an oxidant under transition metal- additive-free conditions. The broad substrate scope, good functional group tolerance, excellent regioselectivity, air tolerant conditions make this process favorable modification scaffold enrich phosphorylated 7-DAP compounds further biological evaluation.

Language: Английский

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Potential applications of JAK inhibitors, clinically approved drugs against autoimmune diseases, in cancer therapy

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 3, 2024

Disturbances in immunoregulation may lead to both cancer and autoimmune diseases. Many therapeutic drugs for diseases also display anti-tumor efficacy. The Janus kinase/signal transducer activator of transcription signaling pathways are involved the secretion more than 50 distinct cytokines, which have critical roles inducing tumorigenesis. Thus, kinases become classical immunotherapeutic targets immune disease. More 70 kinase inhibitors been approved as immunomodulatory clinical use, 12 used treatment This systematic review aims elucidate role clinically that were primarily designed their potential translation treatments.

Language: Английский

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