Discovery of Pamiparib (BGB-290), a Potent and Selective Poly (ADP-ribose) Polymerase (PARP) Inhibitor in Clinical Development

  • J Med Chem. 2020 Dec 24;63(24):15541-15563. doi: 10.1021/acs.jmedchem.0c01346.
Hexiang Wang ,  Bo Ren ,  Ye Liu ,  Beibei Jiang ,  Yin Guo ,  Min Wei ,  Lusong Luo ,  Xianzhao Kuang ,  Ming Qiu ,  Lei Lv ,  Hong Xu ,  Ruipeng Qi ,  Huibin Yan ,  Dexu Xu ,  Zhiwei Wang ,  Chang-Xin Huo ,  Yutong Zhu ,  Yuan Zhao ,  Yiyuan Wu ,  Zhen Qin ,  Dan Su ,  Tristin Tang ,  Fan Wang ,  Xuebing Sun ,  Yingcai Feng ,  Hao Peng ,  Xing Wang ,  Yajuan Gao ,  Yong Liu ,  Wenfeng Gong ,  Fenglong Yu ,  Xuesong Liu ,  Lai Wang ,  Changyou Zhou
PMID: 33264017 DOI: 10.1021/acs.jmedchem.0c01346
Abstract

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.