Celgene Corporation , 10300 Campus Pointe Drive, Suite 100, San Diego, California 92121, United States.
J Med Chem. 2017 Nov 9;60(21):8989-9002. doi: 10.1021/acs.jmedchem.7b01223. Epub 2017 Oct 27.
Triple negative breast cancer (TNBC) remains a serious unmet medical need with discouragingly high relapse rates. We report here the synthesis and structure-activity relationship (SAR) of a novel series of 2,4,5-trisubstituted-7H-pyrrolo[2,3-d]pyrimidines with potent activity against TNBC tumor cell lines. These compounds were discovered from a TNBC phenotypic screen and possess a unique dual inhibition profile targeting TTK (mitotic exit) and CLK2 (mRNA splicing). Design and optimization, driven with a TNBC tumor cell assay, identified potent and selective compounds with favorable in vitro and in vivo activity profiles and good iv PK properties. This cell-based driven SAR produced compounds with strong single agent in vivo efficacy in multiple TNBC xenograft models without significant body weight loss. These data supported the nomination of CC-671 into IND-enabling studies as a single agent TNBC therapy.
三阴性乳腺癌（TNBC）仍然是一种严重的未满足的医疗需求，其复发率高得令人沮丧。我们在这里报告了一系列新型 2,4,5-三取代-7H-吡咯并[2,3-d]嘧啶的合成和构效关系（SAR），这些化合物对 TNBC 肿瘤细胞系具有很强的活性。这些化合物是从 TNBC 表型筛选中发现的，具有针对 TTK（有丝分裂退出）和 CLK2（mRNA 剪接）的独特双重抑制特性。基于 TNBC 肿瘤细胞测定的设计和优化确定了具有良好体外和体内活性特征以及良好 iv PK 特性的有效且选择性的化合物。这种基于细胞的 SAR 产生了具有强体内单一活性的化合物，在多种 TNBC 异种移植模型中没有明显的体重减轻。这些数据支持将 CC-671 作为单一药物 TNBC 治疗药物提名进行 IND 可行性研究。
