Elsner Jan, Cashion Dan, Robinson Dale, Bahmanyar Sogole, Tehrani Lida, Fultz Kimberly E, Narla Rama Krishna, Peng Xiaohui, Tran Tam, Apuy Julius, LeBrun Laurie, Leftheris Katerina, Boylan John F, Zhu Dan, Riggs Jennifer R
Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States.
J Med Chem. 2021 Sep 9;64(17):12670-12679. doi: 10.1021/acs.jmedchem.1c00635. Epub 2021 Aug 30.
TTK is an essential spindle assembly checkpoint enzyme in many organisms. It plays a central role in tumor cell proliferation and is aberrantly overexpressed in a wide range of tumor types. We recently reported on a series of potent and selective TTK inhibitors with strong antiproliferative activity in triple negative breast cancer (TNBC) cell lines (: TTK IC = 3.0 nM; CAL-51 IC = 84.0 nM). Inspired by previously described potent tricyclic TTK inhibitor (TTK IC = 0.9 nM), we embarked on a structure-enabled design and optimization campaign to identify an improved series with excellent potency, TTK selectivity, solubility, CYP inhibition profile, and in vivo efficacy in a TNBC xenograft model. These efforts culminated in the discovery of (TTK IC = 3.0 nM; CAL-51 IC = 16.0 nM), which showed significant single-agent efficacy when dosed iv in a TNBC xenograft model without body weight loss.
TTK是许多生物体中一种重要的纺锤体组装检查点酶。它在肿瘤细胞增殖中起核心作用，并且在多种肿瘤类型中异常过度表达。我们最近报道了一系列在三阴性乳腺癌（TNBC）细胞系中具有强大抗增殖活性的强效且选择性的TTK抑制剂（：TTK IC = 3.0 nM；CAL-51 IC = 84.0 nM）。受先前描述的强效三环TTK抑制剂（TTK IC = 0.9 nM）的启发，我们开展了一项基于结构的设计和优化工作，以确定一个在TNBC异种移植模型中具有优异效力、TTK选择性、溶解度、CYP抑制谱和体内疗效的改进系列。这些努力最终发现了（TTK IC = 3.0 nM；CAL-51 IC = 16.0 nM），其在TNBC异种移植模型中静脉给药时显示出显著的单药疗效，且无体重减轻。
