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Highly Selective Inhibition of Tyrosine Kinase 2 (TYK2) for the Treatment of Autoimmune Diseases: Discovery of the Allosteric Inhibitor BMS-986165.

Author: AranibarNelly, BurkeJames R, CarterPercy H, ChaudhryCharu, ChengLihong, ChimalakondaAnjaneya, ChineyManoj, D'ArienzoCelia, GilloolyKathleen, HeimrichElizabeth, HuangChristine, KempsonJames, KhanJaved, LinShuqun, LombardoLouis, McIntyreKim W, MoslinRyan, MulliganDawn, PittsWilliam J, RuzanovMax, ShusterDavid, SpergelSteven, StrnadJoann, SunHuadong, TokarskiJohn S, TredupJeffrey, WeinsteinDavid S, WrobleskiStephen T, XieDianlin, YangXiaoxia, ZhangYanlei, Zupa-FernandezAdriana

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Overview

This article discusses the development of BMS-986165, a highly selective and potent allosteric inhibitor of TYK2, a member of the JAK family of kinases. Targeting the TYK2 pseudokinase (JH2) domain led to a compound with unprecedented JAK isoform and kinome selectivity, excellent pharmacokinetic properties, minimal profiling liabilities, and efficacy in several murine models of autoimmune disease. This compound has been advanced as the first pseudokinase-directed therapeutic in clinical development for autoimmune diseases.
Paper Details　
Original Abstract of the Article :
Small molecule JAK inhibitors have emerged as a major therapeutic advancement in treating autoimmune diseases. The discovery of isoform selective JAK inhibitors that traditionally target the catalytically active site of this kinase family has been a formidable challenge. Our strategy to achieve high...See full text at original site
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引用元：
https://doi.org/10.1021/acs.jmedchem.9b00444

データ提供：米国国立医学図書館（NLM）

Targeting TYK2: A New Approach to Autoimmune Diseases

Autoimmune diseases, conditions in which the immune system mistakenly attacks the body's own tissues, are a major health challenge. Researchers are constantly striving to develop targeted therapies that effectively control these diseases while minimizing side effects. This study introduces a novel approach, targeting the TYK2 pseudokinase domain, to develop selective inhibitors for the treatment of autoimmune diseases.

A Pseudokinase-Directed Strategy

The study reports the discovery of BMS-986165, a highly selective allosteric inhibitor of TYK2, a key player in the immune system. This inhibitor demonstrates exceptional selectivity for TYK2 over other JAK kinases and shows promising efficacy in preclinical models of autoimmune disease.

A New Frontier in Autoimmune Treatment

This research offers a groundbreaking approach to autoimmune disease treatment, targeting the pseudokinase domain of TYK2. The development of BMS-986165 represents a significant step toward more targeted and effective therapies for these debilitating conditions.

Dr.Camel's Conclusion

This research, like a desert explorer discovering a new oasis, offers a promising new direction for autoimmune disease treatment. Targeting the TYK2 pseudokinase domain provides a unique and potentially more effective approach to controlling the immune system's misdirected activity.

Date :
  1. Date Completed 2020-07-06
  2. Date Revised 2021-10-19
Further Info :

Pubmed ID

31318208

DOI: Digital Object Identifier

10.1021/acs.jmedchem.9b00444

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English

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