Han Xingchun, Jiang Min, Zhou Chengang, Zhou Zheng, Xu Zhiheng, Wang Lisha, Mayweg Alexander V, Niu Rui, Jin Tai-Guang, Yang Song
Medicinal Chemistry, Roche Innovation Center Shanghai, Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Medicinal Chemistry, Roche Innovation Center Shanghai, Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Bioorg Med Chem Lett. 2017 Sep 15;27(18):4488-4492. doi: 10.1016/j.bmcl.2017.07.080. Epub 2017 Aug 1.
A fragment library screen was carried out to identify starting points for novel CDK8 inhibitors. Optimization of a fragment hit guided by co-crystal structures led to identification of a novel series of potent CDK8 inhibitors which are highly ligand efficient, kinase selective and cellular active. Compound 16 was progressed to a mouse pharmacokinetic study and showed good oral bioavailability.
开展了片段库筛选以确定新型CDK8抑制剂的起始点。在共晶体结构的指导下对一个片段命中物进行优化，从而鉴定出一系列新型强效CDK8抑制剂，这些抑制剂具有高配体效率、激酶选择性和细胞活性。化合物16进入小鼠药代动力学研究，并显示出良好的口服生物利用度。
