作者
Hexiang Wang,Bo Ren,Ye Liu,Beibei Jiang,Yin Guo,Wei Min,Liang Luo,Xianzhao Kuang,Ming Qiu,Lei Lv,Hongyi Xu,Ruipeng Qi,Hongzhi Yan,Dexu Xu,Zhiwei Wang,Chang‐Xin Huo,Yutong Zhu,Yuan Zhao,Yongwei Wu,Zhen Qin,Dan Su,Tristin Tang,Fan Wang,Xuebing Sun,Yingcai Feng,Peng Hao,Xing Wang,Yajuan Gao,Yong Liu,Wenfeng Gong,Fenglong Yu,Xuesong Liu,Lai Wang,Changyou Zhou
摘要
Poly (ADP-ribose) polymerase (PARP) plays a significant role in DNA repair responses; therefore, this enzyme is targeted by PARP inhibitors in cancer therapy. Here we have developed a number of fused tetra- or pentacyclic dihydrodiazepinoindolone derivatives with excellent PARP enzymatic and cellular PARylation inhibition activities. These efforts led to the identification of pamiparib (BGB-290, 139), which displays excellent PARP-1 and PARP-2 inhibition with IC50 of 1.3 and 0.9 nM, respectively. In a cellular PARylation assay, this compound inhibits PARP activity with IC50 = 0.2 nM. Cocrystal of pamiparib shows similar binding sites with PARP with other PARP inhibitors, but pamiparib is not a P-gp substrate and shows excellent drug metabolism and pharmacokinetics (DMPK) properties with significant brain penetration (17–19%, mice). The compound is currently being investigated in phase III clinical trials as a maintenance therapy in platinum-sensitive ovarian cancer and gastric cancer.