申请人:President and Fellows of Harvard College
公开号:EP3505521A1
公开(公告)日:2019-07-03
Provided herein are compounds of Formula (A), (B), (C), (D) and (E), pharmaceutically acceptable salts, quaternary amine salts, and N-oxides thereof, and pharmaceutical compositions thereof.
Compounds of Formula (A), (B), (C), (D), and (E) are contemplated useful as therapeutics for treating a wide variety of conditions, e.g., including but not limited to, conditions associated with angiogenesis and with CDK8 and/or CDK19 kinase activity. Further provided are methods of inhibiting CDK8 and/or CDK19 kinase activity, methods of modulating the β-catenin pathway, methods of modulating STAT1 activity, methods of modulating the TGFβ/BMP pathway, methods of modulating HIF-1-alpha activity in a cell, and methods of increasing BIM expression to induce apoptosis, using a compound of Formula (A), (B), (C), (D), or (E). Further provided are CDK8 and CDK19 point mutants and methods of use thereof.
本文提供的是式(A)、(B)、(C)、(D)和(E)化合物、其药学上可接受的盐、季胺盐和 N-氧化物及其药物组合物。
式(A)、(B)、(C)、(D)和(E)化合物可考虑用作治疗多种疾病的药物,例如,包括但不限于与血管生成和CDK8和/或CDK19激酶活性相关的疾病。进一步提供了使用式(A)、(B)、(C)、(D)或(E)化合物抑制 CDK8 和/或 CDK19 激酶活性的方法、调节 β-catenin通路的方法、调节 STAT1 活性的方法、调节 TGFβ/BMP 通路的方法、调节细胞中 HIF-1-α 活性的方法以及增加 BIM 表达以诱导细胞凋亡的方法。进一步提供 CDK8 和 CDK19 点突变体及其使用方法。