2. Academic Validation
  3. Design, synthesis, and biological evaluation of novel 2-substituted aniline pyrimidine derivatives as potential and orally bioavailable Mer inhibitors with antitumor activities

Design, synthesis, and biological evaluation of novel 2-substituted aniline pyrimidine derivatives as potential and orally bioavailable Mer inhibitors with antitumor activities

  • Bioorg Chem. 2025 Jul 15:162:108591. doi: 10.1016/j.bioorg.2025.108591.
Jixia Yang 1,  Daowei Huang 2,  Shouying Wang 3,  Chen Wang 4,  Yanbo Wang 5,  Yi Zhou 4,  Zhenhua Shang 6,  Xiaolei Zhou 7
Affiliations

Affiliations

  • 1 School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang 050200, China; Anhui Jing Ming Pharmaceutical Co., Ltd., Xuancheng 242600, China.
  • 2 School of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang 050018, China. Electronic address: huangdaowei321@163.com.
  • 3 School of Food Science and Biology, Hebei University of Science and Technology, Shijiazhuang 050018, China.
  • 4 School of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang 050018, China.
  • 5 Shijiazhuang Vortech Biotech Co., Ltd., Shijiazhuang 050051, China.
  • 6 School of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang 050018, China. Electronic address: zhenhuashang@126.com.
  • 7 School of Food Science and Biology, Hebei University of Science and Technology, Shijiazhuang 050018, China. Electronic address: foxlei@hebust.edu.cn.
PMID: 40403500 DOI: 10.1016/j.bioorg.2025.108591
Abstract

The constitutive overexpression of Mer tyrosine kinase (MerTK), strongly associated with tumorigenesis and progression across multiple malignancies, establishes it as a promising therapeutic target for oncology discovery. In this study, we systematically designed and synthesized a series of 2-substituted aniline pyrimidine derivatives as potent MerTK inhibitors. The lead compound 15f demonstrated excellent inhibitory activity against Mer kinase with an IC50 value of 37.5 ± 2.7 nM, coupled with broad-spectrum antiproliferative activities against A2780, MDA-MB-231, and HCT116 Cancer cell lines. Notably, 15f exhibited minimal hERG liability, addressing critical safety concerns. Mechanistic studies revealed dose-dependent inhibition of Cancer cell migration and induction of Apoptosis, while pharmacokinetic evaluation demonstrated favorable drug-like properties including high AUC, prolonged half-life, and good oral bioavailability (F: 32.4 %). The bioavailability of 15f was significantly higher than that of compound UNC2250 (F: 23 %). These integrated findings position 15f as a structurally novel and multi-faceted MerTK inhibitor for therapeutic application in Cancer patients.

Keywords

2-substitutedaniline pyrimidine; Antitumor; Inhibitors; Mer kinase.

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