7CMW

Complex structure of PARP1 catalytic domain with pamiparib

Summary for 7CMW

• Entry DOI: 10.2210/pdb7cmw/pdb
• Descriptor: Poly [ADP-ribose] polymerase 1, (2R)-14-fluoro-2-methyl-6,9,10,19-tetrazapentacyclo[14.2.1.02,6.08,18.012,17]nonadeca-1(18),8,12(17),13,15-pentaen-11-one, GLYCEROL, ... (4 entities in total)
• Functional Keywords: parp1, pamiparib, bgb-290, transferase, antitumor protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 80037.47

Authors

Feng, Y.C.,Peng, H.,Hong, Y.,Liu, Y. (deposition date: 2020-07-29, release date: 2020-12-16, Last modification date: 2023-11-29)

Primary citation

Wang, H.,Ren, B.,Liu, Y.,Jiang, B.,Guo, Y.,Wei, M.,Luo, L.,Kuang, X.,Qiu, M.,Lv, L.,Xu, H.,Qi, R.,Yan, H.,Xu, D.,Wang, Z.,Huo, C.X.,Zhu, Y.,Zhao, Y.,Wu, Y.,Qin, Z.,Su, D.,Tang, T.,Wang, F.,Sun, X.,Feng, Y.,Peng, H.,Wang, X.,Gao, Y.,Liu, Y.,Gong, W.,Yu, F.,Liu, X.,Wang, L.,Zhou, C.
Discovery of Pamiparib (BGB-290), a Potent and Selective Poly (ADP-ribose) Polymerase (PARP) Inhibitor in Clinical Development.
J.Med.Chem., 63:15541-15563, 2020

PubMed 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, ), which displays excellent PARP-1 and PARP-2 inhibition with IC of 1.3 and 0.9 nM, respectively. In a cellular PARylation assay, this compound inhibits PARP activity with IC = 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.

PubMed: 33264017
DOI: 10.1021/acs.jmedchem.0c01346

Experimental method

X-RAY DIFFRACTION (2.7 Å)