YCH1899, a Highly Effective Phthalazin-1(2)-one Derivative That Overcomes Resistance to Prior PARP Inhibitors.

Poly(ADP-ribose) polymerase inhibitors (PARPi) have significant efficacy in treating BRCA-deficient cancers, although resistance development remains an unsolved challenge. Herein, a series of phthalazin-1(2)-one derivatives with excellent enzymatic inhibitory activity were designed and synthesized, and the structure-activity relationship was explored. Compared with olaparib and talazoparib, compound exhibited distinct antiproliferation activity against olaparib- and talazoparib-resistant cells, with IC values of 0.89 and 1.13 nM, respectively. Studies of the cellular mechanism revealed that retained sensitivity in drug-resistant cells with BRCA1/2 restoration or 53BP1 loss. Furthermore, had acceptable pharmacokinetic properties in rats and showed prominent dose-dependent antitumor activity in olaparib- and talazoparib-resistant cell-derived xenograft models. Overall, this study suggests that is a new-generation antiresistant PARPi that could provide a valuable direction for addressing drug resistance to existing PARPi drugs.