- Discovery of Pamiparib (BGB-290), a Potent and Selective Poly (ADP-ribose) Polymerase (PARP) Inhibitor in Clinical Development
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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.
- 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
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p. 15541 - 15563
(2020/12/22)
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- TREATMENT CANCERS USING A COMBINATION COMPRISING PARP INHIBITORS, TEMOZOLOMIDE AND/OR RADIATION THERAPY
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Disclosed herein is a method for the prevention, delay of progression or treatment of cancer in a subject, comprising administering to the subject in need thereof a PARP inhibitor, particularly, (R) -2-fluoro-10a-methyl-7, 8, 9, 10, 10a, 11-hexahydro-5, 6, 7a, 11-tetraazacyclohepta [def] cyclopenta [a] fluoren-4 (5H) -one, a sesqui-hydrate thereof, or a pharmaceutically acceptable salt thereof, in combination with temozolomide and/or radiation therapy. Also, disclosed a pharmaceutical combination comprising a PARP inhibitor, particularly, (R) -2-fluoro-10a-methyl-7, 8, 9, 10, 10a, 11-hexahydro-5, 6, 7a, 11-tetraazacyclohepta [def] cyclopenta [a] fluoren-4 (5H) -one, a sesqui-hydrate thereof, or a pharmaceutically acceptable salt thereof, in combination with temozolomide and the use thereof.
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Paragraph 0114; 0115
(2019/02/06)
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- CRYSTALLINE FORMS OF SALTS OF FUSED TERA OR PENTA-CYCLIC DIHYDRODIAZEPINOCARAZOLONES, AND USES THEREOF
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Disclosed herein are salts of (R) -2-fluoro-10a-methyl-7, 8, 9, 10, 10a, 11-hexahydro-5, 6, 7a, 11-tetraazacyclohepta [def] cyclopenta [a] fluoren-4 (5H) -one, and crystalline forms (polymorphs) thereof. Also disclosed herein are methods of preparing those crystalline forms, and methods of using at least one of those crystalline forms in treating a cancer responsive to inhibition of PARP, especially a cancer associated with BRCA1/2 mutant activities or other HR deficiencies, in a subject.
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- TREATMENT CANCERS USING COMBINATION COMPRISING PARP INHIBITORS
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Disclosed herein is a method for the prevention, delay of progression or treatment of cancer in a subject, comprising administering to the subject in need thereof a PARP inhibitor, particularly, (R) -2-fluoro-10a-methyl-7, 8, 9, 10, 10a, 11-hexahydro-5, 6, 7a, 11-tetraazacyclohepta [def] cyclopenta [a] fluoren-4 (5H) -one, a sesqui-hydrate thereof, or a pharmaceutically acceptable salt thereof, in combination with an immune checkpoint inhibitor or a chemotherapeutic agent. Also, disclosed a pharmaceutical combination comprising a PARP inhibitor, particularly, (R) -2-fluoro-10a-methyl-7, 8, 9, 10, 10a, 11-hexahydro-5, 6, 7a, 11-tetraazacyclohepta [def] cyclopenta [a] fluoren-4 (5H) -one, a sesqui-hydrate thereof, or a pharmaceutically acceptable salt thereof, in combination with an immune checkpoint inhibitor, or a chemotherapeutic agent and the use thereof.
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Paragraph 0129-0130
(2018/06/16)
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- FUSED TETRA OR PENTA-CYCLIC DIHYDRODIAZEPINOCARBAZOLONES AS PARP INHIBITORS
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Provided are certain fused tetra or penta-cyclic compounds and salts thereof, compositions thereof, and methods of use thereof.
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Paragraph 0335; 0349; 0350
(2018/12/01)
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- FUSED TETRACYCLIC OR FUSED PENTACYCLIC DIHYDRO DIAZEPINO CARBAZOLONE AS PARP INHIBITOR
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PROBLEM TO BE SOLVED: To provide a specific fused tetracyclic or fused pentacyclic compound, and its salt, its composition, and a method for use thereof. SOLUTION: The present invention provides a compound represented by formula (I), its stereoisomer and pharmaceutically acceptable salt, where RN is H, alkyl or the like; X is C, N, O or S; m and n independently represent an integer of 0-3; t is an integer of 0-3; R1-R8 are H, an alkyl group, an alkenyl group, a heterocyclyl group and the like. SELECTED DRAWING: None COPYRIGHT: (C)2017,JPOandINPIT
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Paragraph 0191
(2017/06/24)
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- FUSED TETRA OR PENTA-CYCLIC DIHYDRODIAZEPINOCARBAZOLONES AS PARP INHIBITORS
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Provided are certain fused tetra or penta-cyclic compounds and salts thereof, compositions thereof, and methods of use thereof.
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- FUSED TETRA OR PENTA-CYCLIC DIHYDRODIAZEPINOCARBAZOLONES AS PARP INHIBITORS
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Provided are certain fused tetra or penta-cyclic compounds and salts thereof, compositions thereof, and methods of use thereof.
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Page/Page column 74
(2013/07/19)
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