Discovery of Novel 2,4-Dianilinopyrimidine Derivatives Containing 4-(Morpholinomethyl)phenyl and N-Substituted Benzamides as Potential FAK Inhibitors and Anticancer Agents

• Published in: Molecules (Basel, Switzerland) Vol. 26; no. 14; p. 4187
• Main Authors: Han, Chun, Shen, Kemin, Wang, Shijun, Wang, Zhijun, Su, Feng, Wu, Xi, Hu, Xiaoqin, Li, Mengyao, Han, Jing, Wu, Lintao
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 09.07.2021; MDPI
• Subjects: 2,4-dianilinopyrimidine; 4-(morpholinomethyl)phenyl; Angiogenesis; anticancer; Apoptosis; Binding sites; Cell cycle; Clinical trials; Design; FAK inhibitor; Focal adhesion kinase; G2 phase; Inhibitors; Kinases; Lead compounds; molecular docking; N-substituted benzamides; Ovarian cancer; Proteins; Substitutes
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules26144187

Focal adhesion kinase (FAK) is responsible for the development and progression of various malignancies. With the aim to explore novel FAK inhibitors as anticancer agents, a series of 2,4-dianilinopyrimidine derivatives 8a–8i and 9a–9g containing 4-(morpholinomethyl)phenyl and N-substituted benzamides have been designed and synthesized. Among them, compound 8a displayed potent anti-FAK activity (IC50 = 0.047 ± 0.006 μM) and selective antiproliferative effects against H1975 (IC50 = 0.044 ± 0.011 μM) and A431 cells (IC50 = 0.119 ± 0.036 μM). Furthermore, compound 8a also induced apoptosis in a dose-dependent manner, arresting the cells in S/G2 phase and inhibiting the migration of H1975 cells, all of which were superior to those of TAE226. The docking analysis of compound 8a was performed to elucidate its possible binding modes with FAK. These results established 8a as our lead compound to be further investigated as a potential FAK inhibitor and anticancer agent.