Design, synthesis, and biological evaluation of novel potent dual Mer/c-Met inhibitors based on structural optimization

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-09-20 DOI:10.1016/j.bmcl.2025.130415

Lihong Duan , Xiaoyu Meng , Fang Li , Chen Wang , Ying Wu , Daowei Huang , Zhiwei Li

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Abstract

Mer and c-Met kinases are frequently co-overexpressed in diverse malignancies, where their concurrent inhibition offers potential for synergetic antitumor efficacy while mitigating toxicity risks associated with single-target therapy. Building upon our previously identified lead compound, we designed and synthesized novel derivatives targeting dual Mer/c-Met inhibition. Among these, compound 17j emerged as a potent dual inhibitor, demonstrating IC₅₀ values of 1.00 ± 0.14 nM (Mer) and 19.00 ± 3.23 nM (c-Met). This agent exhibited robust antiproliferative activity against HCT116, A2780, and PC-3 cancer cell lines, coupled with favorable safety profiles including hERG liability. Notably, 17j displayed exceptional metabolic stability in human liver microsomes (t_1/2 = 72.6 min) over compound 17c. Mechanistic studies confirmed its dose-dependent cytotoxicity and significant suppression of HCT116 cell migration. Collectively, these findings position 17j as a promising therapeutic candidate for Mer/c-Met driven cancers.

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基于结构优化的新型高效双Mer/c-met抑制剂的设计、合成和生物学评价。

Mer和c-Met激酶在多种恶性肿瘤中经常共过表达，它们的同时抑制提供了潜在的协同抗肿瘤功效，同时减轻了与单靶点治疗相关的毒性风险。在我们之前鉴定的先导化合物的基础上，我们设计并合成了新的靶向双Mer/c-Met抑制的衍生物。其中，化合物17j是一种有效的双抑制剂，IC50值分别为1.00 ± 0.14 nM （Mer）和19.00 ± 3.23 nM （c-Met）。该药物对HCT116、A2780和PC-3癌细胞具有强大的抗增殖活性，同时具有良好的安全性，包括hERG敏感性。值得注意的是，17j在人肝微粒体中表现出比化合物17c更好的代谢稳定性（t1/2 = 72.6 min）。机制研究证实其剂量依赖性细胞毒性和显著抑制HCT116细胞迁移。总的来说，这些发现将17j定位为Mer/c-Met驱动型癌症的有希望的治疗候选者。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.