Design, synthesis and biological evaluation of novel PARP inhibitors against acquired drug-resistance.

PARP1 is the most extensive studied member of the PARPs and plays a critical role in maintaining genomic stability. The discovery of the synthetic lethality mechanism has promoted the development of PARPi. However, as the indication of PARPi expands, the issue of drug-resistance urgently needs to be addressed. Herein, through systematic optimization of YCH1899, a series of novel PARPi were designed and synthesized. Among them, YCH3292 not only exhibited robust antiproliferative activity against Capan-1/TP cells (IC50 = 0.23 nM), but also possessed an acceptable pharmacokinetic profile. Studies on the cellular mechanism revealed that it could induce DSB and activate innate immune signaling pathways. More importantly, YCH3292 was determined to be an attractive lead compound, which could overcome acquired resistance to existing PARPi and elicit antitumor immune responses in mouse tumor models.