帕米帕利（BGB-290）的发现，一种在临床开发中具有强大和选择性的聚（ADP-核糖）聚合酶（PARP）抑制剂。
Discovery of Pamiparib (BGB-290), a Potent and Selective Poly (ADP-ribose) Polymerase (PARP) Inhibitor in Clinical Development.
出版信息
J Med Chem. 2020 Dec 24;63(24):15541-15563. doi: 10.1021/acs.jmedchem.0c01346. Epub 2020 Dec 2.
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.
聚（ADP-核糖）聚合酶（PARP）在 DNA 修复反应中发挥重要作用；因此，这种酶是癌症治疗中 PARP 抑制剂的作用靶点。在这里，我们开发了一系列具有优异的 PARP 酶和细胞 PAR 化抑制活性的融合四氢或五氢二氮杂并吲哚酮衍生物。这些努力导致了 pamiparib（BGB-290， ）的鉴定，它对 PARP-1 和 PARP-2 的抑制具有优异的 IC 分别为 1.3 和 0.9 nM。在细胞 PAR 化测定中，该化合物对 PARP 的抑制活性具有 IC = 0.2 nM。pamiparib 的共晶与其他 PARP 抑制剂的 PARP 具有相似的结合位点，但 pamiparib 不是 P-糖蛋白的底物，并且具有出色的药物代谢动力学（DMPK）特性，具有显著的脑穿透性（17-19%，小鼠）。该化合物目前正在 III 期临床试验中作为铂敏感卵巢癌和胃癌的维持治疗进行研究。
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