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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Properties of FDA-approved small molecule protein kinase inhibitors: A 2024 update

Pharmacological Research, Journal Year: 2024, Volume and Issue: 200, P. 107059 - 107059

Published: Jan. 11, 2024

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 80 FDA-approved therapeutic agents that target about two dozen different kinases and seven these drugs were approved 2023. Of drugs, thirteen protein-serine/threonine kinases, four directed against dual specificity (MEK1/2), twenty block nonreceptor protein-tyrosine 43 inhibit receptor kinases. The data indicate 69 prescribed for treatment neoplasms. Six (abrocitinib, baricitinib, deucravacitinib, ritlecitinib, tofacitinib, upadacitinib) used inflammatory (atopic dermatitis, rheumatoid arthritis, psoriasis, alopecia areata, ulcerative colitis). nearly multiple diseases. following received FDA approval 2023: capivasertib (HER2-positive breast cancer), fruquintinib (metastatic colorectal momelotinib (myelofibrosis), pirtobrutinib (mantle cell lymphoma, chronic lymphocytic leukemia, small lymphoma), quizartinib (Flt3-mutant acute myelogenous leukemia), repotrectinib (ROS1-positive lung ritlecitinib (alopecia areata). All orally effective with exception netarsudil, temsirolimus, trilaciclib. This review summarizes physicochemical properties all molecule inhibitors molecular weight, number hydrogen bond donors/acceptors, polar surface area, potency, solubility, lipophilic efficiency, ligand efficiency.

Language: Английский

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Deucravacitinib is an allosteric TYK2 protein kinase inhibitor FDA-approved for the treatment of psoriasis

Pharmacological Research, Journal Year: 2023, Volume and Issue: 189, P. 106642 - 106642

Published: Feb. 6, 2023

Psoriasis is a heterogeneous, inflammatory, autoimmune skin disease that affects up to 2% of the world's population. There are many treatment modalities including topical medicines, ultraviolet light therapy, monoclonal antibodies, and several oral medications. Cytokines play central role in pathogenesis this disorder TNF-α, (tumor necrosis factor-α) IL-17A (interleukin-17A), IL-17F, IL-22, IL-23. Cytokine signaling involves transduction mediated by JAK-STAT pathway. four JAKS (JAK1/2/3 TYK2) six STATS (signal transducer activators transcription). Janus kinases contain an inactive JH2 domain aminoterminal active JH1 domain. Under basal conditions, inhibits activity Deucravacitinib orally effective N-trideuteromethyl-pyridazine derivative targets stabilizes TYK2 thereby blocks activity. Seven other JAK inhibitors, which target family domain, prescribed for neoplastic inflammatory diseases. The use deuterium trimethylamide decreases rate demethylation slows production metabolite against variety addition TYK2. A second unique aspect development deucravacitinib targeting pseudokinase rather specific its toxic effects much less than those FDA-approved inhibitors. successful may stimulate additional ligands kinase families as well.

Language: Английский

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Small molecule inhibitors of RORγt for Th17 regulation in inflammatory and autoimmune diseases

Journal of Pharmaceutical Analysis, Journal Year: 2023, Volume and Issue: 13(6), P. 545 - 562

Published: May 20, 2023

As a ligand-dependent transcription factor, retinoid-associated orphan receptor γt (RORγt) that controls T helper (Th) 17 cell differentiation and interleukin (IL)-17 expression plays critical role in the progression of several inflammatory autoimmune conditions. An emerging novel approach to therapy these diseases thus involves controlling transcriptional capacity RORγt decrease Th17 development IL-17 production. Several inhibitors including both antagonists inverse agonists have been discovered regulate activity by binding orthosteric- or allosteric-binding sites ligand-binding domain. Some small-molecule entered clinical evaluations. Therefore, current review, regulation Th17-related was highlighted. Notably, recently developed were summarized, with an emphasis on their optimization from lead compounds, efficacy, toxicity, mechanisms action, trials. The limitations this area also discussed facilitate future research.

Language: Английский

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Efficacy and tolerability of oral upadacitinib monotherapy in patients with recalcitrant vitiligo

Journal of the American Academy of Dermatology, Journal Year: 2023, Volume and Issue: 89(6), P. 1257 - 1259

Published: July 28, 2023

Language: Английский

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Ruxolitinib induces apoptosis and pyroptosis of anaplastic thyroid cancer via the transcriptional inhibition of DRP1-mediated mitochondrial fission

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(2)

Published: Feb. 9, 2024

Abstract Anaplastic thyroid carcinoma (ATC) has a 100% disease-specific mortality rate. The JAK1/2-STAT3 pathway presents promising target for treating hematologic and solid tumors. However, it is unknown whether the activated in ATC, anti-cancer effects mechanism of action its inhibitor, ruxolitinib (Ruxo, clinical JAK1/2 inhibitor), remain elusive. Our data indicated that signaling significantly upregulated ATC tumor tissues than normal papillary cancer tissues. Apoptosis GSDME-pyroptosis were observed cells following vitro vivo administration Ruxo. Mechanistically, Ruxo suppresses phosphorylation STAT3, resulting repression DRP1 transactivation causing mitochondrial fission deficiency. This deficiency essential activating caspase 9/3-dependent apoptosis GSDME-mediated pyroptosis within cells. In conclusion, our findings indicate directly regulated transactivated by STAT3; this exhibits novel crucial aspect on regulation dynamics. transcriptional inhibition hampered division triggered through mechanisms. These results provide compelling evidence potential therapeutic effectiveness ATC.

Language: Английский

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Mechanisms and therapeutic prospect of the JAK-STAT signaling pathway in liver cancer

Molecular and Cellular Biochemistry, Journal Year: 2024, Volume and Issue: 480(1), P. 1 - 17

Published: March 22, 2024

Language: Английский

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An Antiherpesviral Host-Directed Strategy Based on CDK7 Covalently Binding Drugs: Target-Selective, Picomolar-Dose, Cross-Virus Reactivity

Pharmaceutics, Journal Year: 2024, Volume and Issue: 16(2), P. 158 - 158

Published: Jan. 23, 2024

The repertoire of currently available antiviral drugs spans therapeutic applications against a number important human pathogens distributed worldwide. These include cases the pandemic severe acute respiratory coronavirus type 2 (SARS-CoV-2 or COVID-19), immunodeficiency virus 1 (HIV-1 AIDS), and pregnancy- posttransplant-relevant cytomegalovirus (HCMV). In almost all cases, approved therapies are based on direct-acting antivirals (DAAs), but their benefit, particularly in long-term applications, is often limited by induction viral drug resistance side effects. issues might be addressed additional use host-directed (HDAs). As strong input from experiences with cancer therapies, host protein kinases may serve as HDA targets mechanistically new drugs. study demonstrates such novel strategy targeting major virus-supportive kinase CDK7. Importantly, this focuses highly selective, 3D structure-derived CDK7 inhibitors carrying warhead moiety that mediates covalent target binding. summary, main experimental findings follows: (1) vitro verification inhibition selectivity confirms covalent-binding principle (by CDK-specific assays), (2) pronounced efficacies hit compounds (in cultured cell-based infection models) half-maximal effective concentrations reach down to picomolar levels, (3) potency strains reporter-expressing recombinants HCMV (using assays primary fibroblasts), (4) activity further herpesviruses animal CMVs VZV, (5) unique mechanistic properties an immediate block replication directed early (determined Western blot detection marker proteins), (6) substantial synergism combination MBV (measured Loewe additivity fixed-dose assay), (7) sensitivity clinically relevant mutants ganciclovir markers. Combined, data highlight huge developmental potential concept utilizing covalently binding inhibitors.

Language: Английский

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STAT3 Inhibitors: A Novel Insight for Anticancer Therapy of Pancreatic Cancer

Biomolecules, Journal Year: 2022, Volume and Issue: 12(10), P. 1450 - 1450

Published: Oct. 9, 2022

The signal transducer and activator of transcription (STAT) is a family intracellular cytoplasmic factors involved in many biological functions mammalian transduction. Among them, STAT3 cell proliferation, differentiation, apoptosis, inflammatory responses. Despite the advances treatment pancreatic cancer past decade, prognosis for patients with remains poor. has been shown to play pro-cancer role variety cancers, inhibitors are used pre-clinical clinical studies. We reviewed relationship between latest results on use cancer, aim providing insights ideas around new generation chemotherapeutic modalities cancer.

Language: Английский

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