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

Pharmacological Research, Год журнала: 2022, Номер 187, С. 106552 - 106552

Опубликована: Ноя. 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.

Язык: Английский

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A Comprehensive Overview of Globally Approved JAK Inhibitors

Pharmaceutics, Год журнала: 2022, Номер 14(5), С. 1001 - 1001

Опубликована: Май 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

Язык: Английский

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

Pharmacological Research, Год журнала: 2024, Номер 200, С. 107059 - 107059

Опубликована: Янв. 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.

Язык: Английский

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A small-molecule TNIK inhibitor targets fibrosis in preclinical and clinical models

Nature Biotechnology, Год журнала: 2024, Номер unknown

Опубликована: Март 8, 2024

Abstract Idiopathic pulmonary fibrosis (IPF) is an aggressive interstitial lung disease with a high mortality rate. Putative drug targets in IPF have failed to translate into effective therapies at the clinical level. We identify TRAF2- and NCK-interacting kinase (TNIK) as anti-fibrotic target using predictive artificial intelligence (AI) approach. Using AI-driven methodology, we generated INS018_055, small-molecule TNIK inhibitor, which exhibits desirable drug-like properties activity across different organs vivo through oral, inhaled or topical administration. INS018_055 possesses anti-inflammatory effects addition its profile, validated multiple studies. Its safety tolerability well pharmacokinetics were randomized, double-blinded, placebo-controlled phase I trial (NCT05154240) involving 78 healthy participants. A separate China, CTR20221542, also demonstrated comparable pharmacokinetic profiles. This work was completed roughly 18 months from discovery preclinical candidate nomination demonstrates capabilities of our generative drug-discovery pipeline.

Язык: Английский

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Targeting the PI3K/AKT/mTOR Signaling Pathway in the Treatment of Human Diseases: Current Status, Trends, and Solutions

Journal of Medicinal Chemistry, Год журнала: 2022, Номер 65(24), С. 16033 - 16061

Опубликована: Дек. 12, 2022

The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is one the most important intracellular pathways involved in cell proliferation, growth, differentiation, and survival. Therefore, this route a prospective biological for treating various human diseases, such as tumors, neurodegenerative pulmonary fibrosis, diabetes. An increasing number clinical studies emphasize necessity developing novel molecules targeting PI3K/AKT/mTOR pathway. This review focuses on recent advances ATP-competitive inhibitors, allosteric covalent proteolysis-targeting chimeras against pathway, highlights possible solutions overcoming toxicities acquired drug resistance currently available drugs. We also provide recommendations future design development promising drugs

Язык: Английский

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Protein kinases: drug targets for immunological disorders

Nature reviews. Immunology, Год журнала: 2023, Номер 23(12), С. 787 - 806

Опубликована: Май 15, 2023

Язык: Английский

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Rule of five violations among the FDA-approved small molecule protein kinase inhibitors

Pharmacological Research, Год журнала: 2023, Номер 191, С. 106774 - 106774

Опубликована: Апрель 17, 2023

Because genetic alterations including mutations, overexpression, translocations, and dysregulation of protein kinases are involved in the pathogenesis many illnesses, this enzyme family is target drug discovery programs pharmaceutical industry. Overall, US FDA has approved 74 small molecule kinase inhibitors, nearly all which orally effective. Of drugs, thirty-nine block receptor protein-tyrosine kinases, nineteen nonreceptor twelve directed against protein-serine/threonine four dual specificity kinases. The data indicate that 65 these medicinals for management neoplasms (51 solid tumors such as breast, colon, lung cancers, eight nonsolid leukemia, six both types tumors). Nine FDA-approved inhibitors form covalent bonds with their enzymes they accordingly classified TCIs (targeted inhibitors). Medicinal chemists have examined physicochemical properties drugs Lipinski's rule five (Ro5) a computational procedure used to estimate solubility, membrane permeability, pharmacological effectiveness drug-discovery setting. It relies on parameters molecular weight, number hydrogen bond donors acceptors, Log partition coefficient. Other important descriptors include lipophilic efficiency, polar surface area, rotatable aromatic rings. We tabulated other inhibitors. 30 fail comply five.

Язык: Английский

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Fluorine-a small magic bullet atom in the drug development: perspective to FDA approved and COVID-19 recommended drugs

Chemical Papers, Год журнала: 2023, Номер 77(8), С. 4085 - 4106

Опубликована: Апрель 13, 2023

Язык: Английский

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A review: FDA-approved fluorine-containing small molecules from 2015 to 2022

European Journal of Medicinal Chemistry, Год журнала: 2023, Номер 260, С. 115758 - 115758

Опубликована: Авг. 24, 2023

Язык: Английский

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

Pharmacological Research, Год журнала: 2022, Номер 183, С. 106362 - 106362

Опубликована: Июль 22, 2022

Язык: Английский

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