Department of Medicinal Chemistry, Amgen, Inc., 360 Binney Street, Cambridge, Massachusetts 02142, USA.
J Med Chem. 2011 Dec 22;54(24):8440-50. doi: 10.1021/jm200911r. Epub 2011 Nov 16.
Developing Janus kinase 2 (Jak2) inhibitors has become a significant focus for small molecule drug discovery programs in recent years due to the identification of a Jak2 gain-of-function mutation in the majority of patients with myeloproliferative disorders (MPD). Here, we describe the discovery of a thienopyridine series of Jak2 inhibitors that culminates with compounds showing 100- to >500-fold selectivity over the related Jak family kinases in enzyme assays. Selectivity for Jak2 was also observed in TEL-Jak cellular assays, as well as in cytokine-stimulated peripheral blood mononuclear cell (PBMC) and whole blood assays. X-ray cocrystal structures of 8 and 19 bound to the Jak2 kinase domain aided structure-activity relationship efforts and, along with a previously reported small molecule X-ray cocrystal structure of the Jak1 kinase domain, provided structural rationale for the observed high levels of Jak2 selectivity.
近年来，由于在大多数骨髓增殖性疾病（MPD）患者中发现了 Jak2 获得性功能突变，开发 Janus 激酶 2（Jak2）抑制剂已成为小分子药物发现计划的重点。在这里，我们描述了噻吩并吡啶系列 Jak2 抑制剂的发现，该系列最终得到的化合物在酶测定中对相关 Jak 家族激酶的选择性高达 100 至> 500 倍。在 TEL-Jak 细胞测定中以及在细胞因子刺激的外周血单核细胞（PBMC）和全血测定中也观察到了 Jak2 的选择性。与 Jak2 激酶结构域结合的 8 和 19 的 X 射线共晶结构有助于进行结构-活性关系研究，并且与先前报道的 Jak1 激酶结构域的小分子 X 射线共晶结构一起，为观察到的高水平 Jak2 选择性提供了结构依据。
