Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China.
J Med Chem. 2020 Apr 23;63(8):3956-3975. doi: 10.1021/acs.jmedchem.9b01784. Epub 2020 Apr 7.
The bromodomain and extra-terminal (BET) family proteins have recently emerged as promising drug targets for cancer therapy. In this study, identification of an 8-methyl-pyrrolo[1,2-]pyrazin-1(2)-one fragment () as a new binder to the BET bromodomains and the subsequent incorporation of fragment to the scaffold of , which recently entered Phase I clinical trials, enabled the generation of a series of highly potent BET bromodomain inhibitors. Further druggability optimization led to the discovery of compound as a potential preclinical candidate. Significantly, compared with , which exhibits a 63-fold selectivity for BRD4(1) over EP300, compound demonstrates an excellent selectivity for the BET bromodomain family over other bromodomains, with an ∼1500-fold selectivity for BRD4(1) over EP300. Orally administered achieves a complete inhibition of tumor growth with a tumor growth inhibition (TGI) of 99.7% accompanied by good tolerability.
溴结构域和末端（BET）家族蛋白最近已成为癌症治疗中很有前途的药物靶点。在这项研究中，确定 8-甲基吡咯并[1,2-]吡嗪-1(2)-酮片段（）是 BET 溴结构域的新型结合物，随后将片段整合到最近进入 I 期临床试验的支架中，从而产生了一系列高活性 BET 溴结构域抑制剂。进一步的可用药性优化导致发现化合物作为潜在的临床前候选药物。值得注意的是，与选择性为 BRD4(1) 对 EP300 的 63 倍相比，化合物对 BET 溴结构域家族的选择性优于其他溴结构域，对 BRD4(1) 的选择性约为 EP300 的 1500 倍。口服给予化合物可完全抑制肿瘤生长，肿瘤生长抑制（TGI）为 99.7%，同时具有良好的耐受性。
