Rational Design of PARP1/c-Met Dual Inhibitors for Overcoming PARP1 Inhibitor Resistance Induced by c‑Met Overexpression

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.