Discovery, Synthesis, and Biological Evaluation of 1,3,4,5-Tetrahydro-6 H -pyrano[4,3- c ]isoquinolin-6-one Derivatives as Novel and Highly Selective PARP1
Zhongning Guo, Rongrong Sun, Linyu Yang, Yurong Zou, Tao Guo, Ziyan Ma, Shuai Liu, Peng Wang, Yongting Yuan, Lingping Ye, Yonglin Chen, Songhui Qin, Na Li, Peng Bai, Quan Yuan, Wei Yan, Weichen Bo, Taijin Wang, Jiankun Hu, Lijuan ChenAbstract
Developing highly selective PARP1 inhibitors is a promising strategy to improve the therapeutic window compared with dual PARP1/2 inhibitors. Through structure-guided design and optimization, we developed (R)-A17, a novel, highly selective PARP1 inhibitor featuring a unique tricyclic scaffold. It demonstrates nanomolar enzymatic potency (PARP1 IC50 = 2.4 nM), exceptional 65.8-fold selectivity over PARP2, and robust antiproliferative activity in BRCA-deficient cells. (R)-A17 exhibits favorable pharmacokinetic properties with complete oral bioavailability (F = 100%) in mice. Mechanistically, it selectively inhibits PARP1-mediated PARylation and induces DNA damage and G2/M phase arrest. In vivo, oral administration of (R)-A17 produced dose-dependent antitumor efficacy in BRCA mutant xenograft models, achieving tumor growth inhibition values of 57.8, 86.3, and 91.3% at doses of 0.3, 1, and 3 mg/kg, respectively, while also synergizing effectively with liposomal irinotecan in an HCT116 xenograft model. These results establish (R)-A17 as a promising candidate and validate the design strategy for the next-generation PARP1-targeted therapy.