Celgene Corporation , 10300 Campus Point Drive, Suite 100 , San Diego , California 92121 , United States.
J Med Chem. 2019 May 9;62(9):4401-4410. doi: 10.1021/acs.jmedchem.8b01869. Epub 2019 Apr 30.
Triple negative breast cancer (TNBC) is an aggressive disease with high relapse rates and few treatment options. Outlined in previous publications, we identified a series of potent, dual TTK/CLK2 inhibitors with strong efficacy in TNBC xenograft models. Pharmacokinetic properties and kinome selectivity were optimized, resulting in the identification of a new series of potent, selective, and orally bioavailable TTK inhibitors. We describe here the structure-activity relationship of the 2,4-disubstituted-7 H-pyrrolo[2,3- d]pyrimidine series, leading to significant single agent efficacy in a TNBC xenograft model without body weight loss. The design effort evolving an iv-dosed TTK/CLK2 inhibitor to an orally bioavailable TTK inhibitor is described.
三阴性乳腺癌（TNBC）是一种侵袭性疾病，复发率高，治疗选择有限。在之前的出版物中，我们鉴定了一系列强效的双 TTK/CLK2 抑制剂，它们在 TNBC 异种移植模型中具有很强的疗效。优化了药代动力学特性和激酶组选择性，从而鉴定出了一系列新的强效、选择性和可口服生物利用的 TTK 抑制剂。我们在这里描述了 2,4-二取代-7H-吡咯并[2,3-d]嘧啶系列的构效关系，导致在 TNBC 异种移植模型中具有显著的单药疗效，而无体重减轻。描述了将 iv 给药的 TTK/CLK2 抑制剂设计成可口服生物利用的 TTK 抑制剂的努力。
