Discovery of 2,4-diaminopyrimidine derivatives as potent inhibitors of FAK capable of activating the Hippo pathway for the treatment of esophageal squamous cell carcinoma
- Eur J Med Chem. 2025 Apr 5:287:117328. doi: 10.1016/j.ejmech.2025.117328.
- 1. School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
- 2. School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou, 450001, China.
- 3. The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
- 4. School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China. Electronic address: [email protected].
- 5. School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China. Electronic address: [email protected].
In this work, we report the discovery of 2,4-diaminopyrimidine derivatives bearing a urea moiety as FAK inhibitors capable of activating the Hippo pathway in Esophageal Squamous Cell Carcinoma (ESCC). Extensive structure-activity relationship studies were conducted based on the lead FAK Inhibitor TAE-226 to enhance the inhibitory potency, and the most potent compound 8b (MY-1576) as a FAK Inhibitor ultimately was identified. Compound MY-1576 exhibited potent FAK inhibitory activity, in vitro Anticancer activities, and acceptable PK properties. Notably, MY-1576 could activate the Hippo pathway, resulting in impeding YAP/TAZ regulation. MY-1576 also effectively suppressed the tumor growth in the KYSE30 xenograft mouse models with good safety profiles, and potently down-regulated the autophosphorylation of FAK and the levels of YAP/TAZ in vivo. Taken together, these results indicate that MY-1576, functioning as a FAK Inhibitor capable of activating the Hippo pathway, is a promising candidate against ESCC.