posted on 2024-03-13, 13:08authored byZeren Sun, Lanjie Li, Bingxin Zhai, Mengxuan Hu, Lei Huang, Shihui Huang, Liu Ye, Xiangying Kong, Jie Xu, Jie Bai, Jingjie Yan, Qichen Zhou, Zheqi Hu, Yuchen Zhang, Yuhan Jiang, Yan Zhang, Zhou Qiao, Yi Zou, Yungen Xu, Qihua Zhu
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 (IC50 = 3.3 nM) and c-Met (IC50 = 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.