Henry Sean P, Liosi Maria-Elena, Ippolito Joseph A, Cutrona Kara J, Krimmer Stefan G, Newton Ana S, Schlessinger Joseph, Jorgensen William L
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.
ACS Med Chem Lett. 2022 Apr 21;13(5):819-826. doi: 10.1021/acsmedchemlett.2c00051. eCollection 2022 May 12.
The Janus kinase 2 (JAK2) pseudokinase domain (JH2) is an ATP-binding domain that regulates the activity of the catalytic tyrosine kinase domain (JH1). Dysregulation of JAK2 JH1 signaling caused by the V617F mutation in JH2 is implicated in various myeloproliferative neoplasms. To explore if JAK2 activity can be modulated by a small molecule binding to the ATP site in JH2, we have developed several ligand series aimed at selectively targeting the JAK2 JH2 domain. We report here the evolution of a false virtual screen hit into a new JAK2 JH2 series. Optimization guided by computational modeling has yielded analogues with nanomolar affinity for the JAK2 JH2 domain and >100-fold selectivity for the JH2 domain over the JH1 domain. A crystal structure for one of the potent compounds bound to JAK2 JH2 clarifies the origins of the strong binding and selectivity. The compounds expand the platform for seeking molecules to regulate JAK2 signaling, including V617F JAK2 hyperactivation.
Janus激酶2（JAK2）假激酶结构域（JH2）是一个ATP结合结构域，可调节催化性酪氨酸激酶结构域（JH1）的活性。由JH2中的V617F突变导致的JAK2 JH1信号传导失调与多种骨髓增殖性肿瘤有关。为了探究JAK2活性是否可以通过与JH2中ATP位点结合的小分子来调节，我们开发了几个旨在选择性靶向JAK2 JH2结构域的配体系列。我们在此报告了一个虚拟筛选假阳性命中物演变成一个新的JAK2 JH2系列的过程。由计算模型指导的优化产生了对JAK2 JH2结构域具有纳摩尔亲和力且对JH2结构域比对JH1结构域具有>100倍选择性的类似物。一种与JAK2 JH2结合的强效化合物的晶体结构阐明了强结合和选择性的来源。这些化合物扩展了寻找调节JAK2信号传导的分子的平台，包括V617F JAK2的过度激活。
