1区 · 医学
Article
作者: Wang, Hexiang ; Ren, Bo ; Liu, Ye ; Jiang, Beibei ; Guo, Yin ; Wei, Min ; Luo, Lusong ; Kuang, Xianzhao ; Qiu, Ming ; Lv, Lei ; Xu, Hong ; Qi, Ruipeng ; Yan, Huibin ; Xu, Dexu ; Wang, Zhiwei ; Huo, Chang-Xin ; Zhu, Yutong ; Zhao, Yuan ; Wu, Yiyuan ; Qin, Zhen ; Su, Dan ; Tang, Tristin ; Wang, Fan ; Sun, Xuebing ; Feng, Yingcai ; Peng, Hao ; Wang, Xing ; Gao, Yajuan ; Liu, Yong ; Gong, Wenfeng ; Yu, Fenglong ; Liu, Xuesong ; Wang, Lai ; Zhou, Changyou
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.