Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, United States.
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8066, United States.
J Med Chem. 2020 May 28;63(10):5324-5340. doi: 10.1021/acs.jmedchem.0c00192. Epub 2020 May 8.
Janus kinases (JAKs) are non-receptor tyrosine kinases that are essential components of the JAK-STAT signaling pathway. Associated aberrant signaling is responsible for many forms of cancer and disorders of the immune system. The present focus is on the discovery of molecules that may regulate the activity of JAK2 by selective binding to the JAK2 pseudokinase domain, JH2. Specifically, the Val617Phe mutation in JH2 stimulates the activity of the adjacent kinase domain (JH1) resulting in myeloproliferative disorders. Starting from a non-selective screening hit, we have achieved the goal of discovering molecules that preferentially bind to the ATP binding site in JH2 instead of JH1. We report the design and synthesis of the compounds and binding results for the JH1, JH2, and JH2 V617F domains, as well as five crystal structures for JH2 complexes. Testing with a selective and non-selective JH2 binder on the autophosphorylation of wild-type and V617F JAK2 is also contrasted.
Janus 激酶（JAKs）是非受体酪氨酸激酶，是 JAK-STAT 信号通路的重要组成部分。相关异常信号导致许多形式的癌症和免疫系统紊乱。目前的重点是发现可能通过选择性结合 JAK2 的假激酶结构域 JH2 来调节 JAK2 活性的分子。具体来说，JH2 中的 Val617Phe 突变刺激相邻激酶结构域（JH1）的活性，导致骨髓增生性疾病。从非选择性筛选命中开始，我们已经实现了发现优先与 JH2 而不是 JH1 的 ATP 结合位点结合的分子的目标。我们报告了化合物的设计和合成以及 JH1、JH2 和 JH2 V617F 结构域的结合结果，以及五个 JH2 复合物的晶体结构。还比较了对野生型和 V617F JAK2 的自身磷酸化的选择性和非选择性 JH2 结合物的测试。
