YCH1899, a Highly Effective Phthalazin-1(2<i>H</i>)-one Derivative That Overcomes Resistance to Prior PARP Inhibitors
Yuting Sun, Hui Yang, Jiaqi Yuan, Li‐Min Wang, Shanshan Song, Rongrong Chen, Xubin Bao, Jia Li, Tiantian Yang, Xiaofei Zhang, Qian He, Yong Gan, Ze‐Hong Miao, Jin‐Xue He, Chunhao Yang
Abstract
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 H )-one derivatives with excellent enzymatic inhibitory activity were designed and synthesized, and the structure–activity relationship was explored. Compared with olaparib and talazoparib, compound YCH1899 exhibited distinct antiproliferation activity against olaparib- and talazoparib-resistant cells, with IC 50 values of 0.89 and 1.13 nM, respectively. Studies of the cellular mechanism revealed that YCH1899 retained sensitivity in drug-resistant cells with BRCA1/2 restoration or 53BP1 loss. Furthermore, YCH1899 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 YCH1899 is a new-generation antiresistant PARPi that could provide a valuable direction for addressing drug resistance to existing PARPi drugs.