Discovery of Bicyclo[1.1.1]pentane-based Olaparib derivatives as novel PARP inhibitors: A dual-action strategy targeting DNA damage and immune activation

PARP inhibitors play a crucial role in Cancer therapy, with PARP7 emerging as a promising target for immunotherapy by modulating the cGAS-STING pathway. In this study, the piperazine ring of Olaparib was replaced with a bicyclo[1.1.1]pentane (BCP) scaffold to improve its pharmacological profile. The lead compound B3 exhibited potent dual inhibition against PARP1 (IC₅₀ = 0.6 nM) and PARP7 (IC₅₀ = 7.5 nM), thereby overcoming the PARP7 inactivity of Olaparib. B3 displayed selective antiproliferative activity against BRCA-deficient Cancer cells with minimal toxicity to normal cells. Mechanistically, B3 induced G2/M phase arrest, promoted Apoptosis, elevated ROS levels, disrupted mitochondrial membrane potential, and suppressed PARylation while increasing γH2AX accumulation in HCC1937 cells. Notably, B3 activated the cGAS-STING pathway, upregulating IFN-β and CXCL10 expression in vitro and enhancing CD8⁺ T cell infiltration in a CT26 syngeneic mouse model, demonstrating robust in vivo antitumor efficacy. Furthermore, B3 demonstrated favorable pharmacokinetic properties. This work established the BCP modification strategy as a viable approach for expanding the diversity of PARP inhibitors, offering a dual-mechanism therapeutic strategy that combines targeting the DNA damage response with immunomodulatory effects for synergistic antitumor outcomes.

BCP; Olaparib; PARP1; PARP7; Synergistic antitumor.