Design, Synthesis, and Biological Evaluation of 2-Substituted Aniline Pyrimidine Derivatives as Potent Dual Mer/c-Met Inhibitors


Molecules 29, no. 2 (2024)


Huang, Daowei, Ying Chen, Jixia Yang, Bingyang Zhao, Shouying Wang, Tingting Chai, Jie Cui, Xiaolei Zhou, and Zhenhua Shang



Mer and c-Met kinases, which are commonly overexpressed in various tumors, are ideal targets for the development of antitumor drugs. This study focuses on the design, synthesis, and evaluation of several 2-substituted aniline pyrimidine derivatives as highly potent dual inhibitors of Mer and c-Met kinases for effective tumor treatment. Compound 18c emerged as a standout candidate, demonstrating robust inhibitory activity against Mer and c-Met kinases, with IC50 values of 18.5 ± 2.3 nM and 33.6 ± 4.3 nM, respectively. Additionally, compound 18c displayed good antiproliferative activities on HepG2, MDA-MB-231, and HCT116 cancer cells, along with favorable safety profiles in hERG testing. Notably, it exhibited exceptional liver microsomal stability in vitro, with a half-life of 53.1 min in human liver microsome. Compound 18c also exhibited dose-dependent cytotoxicity and hindered migration of HCT116 cancer cells, as demonstrated in apoptosis and migration assays. These findings collectively suggest that compound 18c holds promise as a dual Mer/c-Met agent for cancer treatment.

Keywords: Q1 2024

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