Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Basel, 4002, Switzerland.
Oncology Drug Discovery, Novartis Institutes for BioMedical Research, Basel, 4002, Switzerland.
ChemMedChem. 2023 Jun 1;18(11):e202300051. doi: 10.1002/cmdc.202300051. Epub 2023 Apr 13.
The inhibition of the YAP-TEAD protein-protein interaction constitutes a promising therapeutic approach for the treatment of cancers linked to the dysregulation of the Hippo signaling pathway. The identification of a class of small molecules which potently inhibit the YAP-TEAD interaction by binding tightly to the Ω-loop pocket of TEAD has previously been communicated. This report details the further multi-parameter optimization of this class of compounds resulting in advanced analogs combining nanomolar cellular potency with a balanced ADME and off-target profile, and efficacy of these compounds in tumor bearing mice is demonstrated for the first time.
抑制 YAP-TEAD 蛋白-蛋白相互作用构成了一种有前途的治疗方法，可用于治疗与 Hippo 信号通路失调相关的癌症。先前已经报道了一类能够通过紧密结合 TEAD 的 Ω 环口袋来强力抑制 YAP-TEAD 相互作用的小分子的鉴定。本报告详细介绍了此类化合物的进一步多参数优化，得到了结合纳米摩尔细胞效力、平衡的 ADME 和脱靶谱的先进类似物，并首次证明了这些化合物在荷瘤小鼠中的疗效。
