Highly Selective Inhibition of Tyrosine Kinase 2 (TYK2) for the Treatment of Autoimmune Diseases: Discovery of the Allosteric Inhibitor BMS-986165
Highly Selective Inhibition of Tyrosine Kinase 2 (TYK2) for the Treatment of Autoimmune Diseases: Discovery of the Allosteric Inhibitor BMS-986165
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DOI：
10.1021/acs.jmedchem.9b00444
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发表时间：
2019-10-24
影响因子：
7.3
通讯作者：
Weinstein, David S.
中科院分区：
文献类型：
--
作者：
Wrobleski, Stephen T.;Moslin, Ryan;Weinstein, David S.
小分子JAK抑制剂已经成为治疗自身免疫性疾病的主要治疗进展。传统上靶向该激酶家族的催化活性位点的亚型选择性JAK抑制剂的发现一直是一个巨大的挑战。我们实现TYK 2高选择性的策略依赖于靶向TYK 2假激酶（JH 2）结构域。在本文中，我们报告了后期优化工作，包括结构指导设计和水置换策略，导致发现BMS-986165（11）作为高亲和力JH 2配体和TYK 2的强效变构抑制剂。除了前所未有的JAK同种型和激酶组选择性之外，11还显示出优异的药代动力学性质，具有最小的分析倾向，并且在几种自身免疫性疾病的鼠模型中有效。在这些发现的基础上，11似乎与所有其他报道的JAK抑制剂不同，并且已经作为临床开发中的第一个假激酶导向治疗剂作为自身免疫性疾病的口服治疗而发展。
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 selectivity for TYK2 relies on targeting the TYK2 pseudokinase (JH2) domain. Herein we report the late stage optimization efforts including a structure-guided design and water displacement strategy that led to the discovery of BMS-986165 (11) as a high affinity JH2 ligand and potent allosteric inhibitor of TYK2. In addition to unprecedented JAK isoform and kinome selectivity, 11 shows excellent pharmacokinetic properties with minimal profiling liabilities and is efficacious in several murine models of autoimmune disease. On the basis of these findings, 11 appears differentiated from all other reported JAK inhibitors and has been advanced as the first pseudokinase-directed therapeutic in clinical development as an oral treatment for autoimmune diseases.