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Discovery of a prominent dual-target DDR1/EGFR inhibitor aimed DDR1/EGFR-positive NSCLC. 2024

Xuebao Wang, and Ying Lu, and Siyu Chen, and Zhaojingtao Zhu, and Yanneng Fu, and Jinxia Zhang, and Jiale He, and Lu Huang, and Lihong Luo, and Weiting Guo, and Zhouyang Xu, and Zixin Xie, and Xuemei Xu, and Yuan Zhang, and Faqing Ye, and Shumei Ma
School of Public Health, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.

This study aimed to develop the first dual-target small molecule inhibitor concurrently targeting Discoidin domain receptor 1 (DDR1) and Epidermal growth factor receptor (EGFR), which play a crucial interdependent roles in non-small cell lung cancer (NSCLC), demonstrating a synergistic inhibitory effect. A series of innovative dual-target inhibitors for DDR1 and EGFR were discovered. These compounds were designed and synthesized using structural optimization strategies based on the lead compound BZF02, employing 4,6-pyrimidine diamine as the core scaffold, followed by an investigation of their biological activities. Among these compounds, D06 was selected and showed micromolar enzymatic potencies against DDR1 and EGFR. Subsequently, compound D06 was observed to inhibit NSCLC cell proliferation and invasion. Demonstrating acceptable pharmacokinetic performance, compound D06 exhibited its anti-tumor activity in NSCLC PC-9/GR xenograft models without apparent toxicity or significant weight loss. These collective results showcase the successful synthesis of a potent dual-targeted inhibitor, suggesting the potential therapeutic efficacy of co-targeting DDR1 and EGFR for DDR1/EGFR-positive NSCLC.

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