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

• Main Authors: Chun Han, Kemin Shen, Shijun Wang, Zhijun Wang, Feng Su, Xi Wu, Xiaoqin Hu, Mengyao Li, Jing Han, Lintao Wu
• Format: Article
• Language: English
• Published: MDPI AG 2021-07-01
• Series: Molecules
• Subjects: FAK inhibitor; 2,4-dianilinopyrimidine; 4-(morpholinomethyl)phenyl; <i>N</i>-substituted benzamides; anticancer; molecular docking
• Online Access: https://www.mdpi.com/1420-3049/26/14/4187
• ISSN: 1420-3049

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 <b>8a</b>–<b>8i</b> and <b>9a</b>–<b>9g</b> containing 4-(morpholinomethyl)phenyl and <i>N</i>-substituted benzamides have been designed and synthesized. Among them, compound <b>8a</b> 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 <b>8a</b> 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 <b>8a</b> was performed to elucidate its possible binding modes with FAK. These results established <b>8a</b> as our lead compound to be further investigated as a potential FAK inhibitor and anticancer agent.