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

Poly(ADP-ribose)polymerase inhibitors (PARPi) have significantefficacy in treating BRCA-deficient cancers, although resistance developmentremains an unsolved challenge. Herein, a series of phthalazin-1(2H)-one derivatives with excellent enzymatic inhibitory activitywere designed and synthesized, and the structure-activity relationshipwas explored. Compared with olaparib and talazoparib, compound YCH1899 exhibited distinct antiproliferation activity againstolaparib- and talazoparib-resistant cells, with IC50 valuesof 0.89 and 1.13 nM, respectively. Studies of the cellular mechanismrevealed that YCH1899 retained sensitivity in drug-resistantcells with BRCA1/2 restoration or 53BP1 loss. Furthermore, YCH1899 had acceptable pharmacokinetic properties in rats and showed prominentdose-dependent antitumor activity in olaparib- and talazoparib-resistantcell-derived xenograft models. Overall, this study suggests that YCH1899 is a new-generation antiresistant PARPi that couldprovide a valuable direction for addressing drug resistance to existingPARPi drugs.