Rational Design, Synthesis, and Biological Evaluation of Novel c‑Met Degraders for Lung Cancer Therapy

Cellular-mesenchymal epithelial transition factor (c-Met) is an attractive target for treating multiple cancers. Despite plentiful c-Met inhibitors have been developed, some issues, including the acquired drug resistance to c-Met inhibitors, have emerged to hamper their application in clinical treatment. Degradation of c-Met offers an opportunity to solve these issues. In this study, we developed a series of c-Met degraders, and the optimal compound 22b can efficiently degrade c-Met with a DC50 value of 0.59 nM in EBC-1 cells. Mechanistic studies revealed that compound 22b induced c-Met degradation via proteasome-mediated pathway. In addition, compound 22b suppressed the proliferation and also induced apoptosis of EBC-1 cells, outperforming the corresponding inhibitor tepotinib. Importantly, compound 22b showed favorable pharmacokinetic properties and significantly induced tumor regression in a xenograft model without obvious toxicity. In brief, this study provided compound 22b as a novel c-Met degrader for lung cancer therapy.细胞间质上皮转换因子（Cellular-mesenchymal epithelial transition factor，c-Met）是治疗多种癌症的极具潜力的靶点。尽管已有大量c-Met抑制剂被研发问世，但包括c-Met抑制剂获得性耐药在内的诸多问题逐渐显现，阻碍了其临床应用。降解c-Met为解决这些难题提供了全新契机。本研究开发了一系列c-Met降解剂，其中最优化合物22b可在EBC-1细胞中高效降解c-Met，其半数降解浓度（DC50）为0.59 nM。机制研究表明，化合物22b通过蛋白酶体介导的通路诱导c-Met降解。此外，化合物22b可抑制EBC-1细胞增殖并诱导其凋亡，效果优于同类抑制剂特泊替尼（tepotinib）。重要的是，化合物22b展现出良好的药代动力学特性，且在异种移植模型中可显著诱导肿瘤消退，未观察到明显毒性。简言之，本研究提出化合物22b作为一种新型c-Met降解剂，用于肺癌治疗。