Rational Design of PARP1/c-Met Dual Inhibitors for Overcoming PARP1 Inhibitor Resistance Induced by c-Met Overexpression
Zeren Sun, Lanjie Li, Bingxin Zhai, Mengxuan Hu, Lei Huang, Shihui Huang, Ye Liu, Xiangying Kong, Jie Xu, Jie Bai, Jingjie Yan, Qichen Zhou, Zheqi Hu, Yuchen Zhang, Yuhan Jiang, Yan Zhang, Qiao Zhou, Yi Zou, Yungen Xu, Qihua Zhu
Abstract
The emergence of resistance to PARP1 inhibitors poses a current therapeutic challenge, necessitating the development of novel strategies to overcome this obstacle. The present study describes the design and synthesis of a series of small molecules that target both PARP1 and c-Met. Among them, compound 16 is identified as a highly potent dual inhibitor, exhibiting excellent inhibitory activities against PARP1 (IC 50 = 3.3 nM) and c-Met (IC 50 = 32.2 nM), as well as demonstrating good antiproliferative effects on HR-proficient cancer cell lines and those resistant to PARP1 inhibitors. Importantly, compound 16 demonstrates superior antitumor potency compared to the PARP1 inhibitor Olaparib and the c-Met inhibitor Crizotinib, either alone or in combination, in MDA-MB-231 and HCT116OR xenograft models. These findings highlight the potential of PARP1/c-Met dual inhibitors for expanding the indications of PARP1 inhibitors and overcoming tumor cells’ resistance to them.