Discovery of Pamiparib (BGB-290), a Potent and Selective Poly (ADP-ribose) Polymerase (PARP) Inhibitor in Clinical Development
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 cellul...
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| Veröffentlicht in: | Journal of medicinal chemistry 2020-12, Vol.63 (24), p.15541-15563 |
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| creator | 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 |
| description | 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. |
| doi_str_mv | 10.1021/acs.jmedchem.0c01346 |
| format | Article |
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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.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.0c01346</identifier><identifier>PMID: 33264017</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Binding Sites ; Carbazoles - chemistry ; Carbazoles - metabolism ; Carbazoles - pharmacology ; Carbazoles - therapeutic use ; Cell Proliferation - drug effects ; Dogs ; Female ; Fluorenes - chemistry ; Fluorenes - metabolism ; Fluorenes - pharmacology ; Fluorenes - therapeutic use ; Half-Life ; Humans ; Indoles - chemistry ; Indoles - metabolism ; Indoles - pharmacology ; Indoles - therapeutic use ; Isoenzymes - antagonists & inhibitors ; Isoenzymes - metabolism ; Mice ; Microsomes - metabolism ; Molecular Docking Simulation ; Neoplasms - drug therapy ; Poly(ADP-ribose) Polymerase Inhibitors - chemistry ; Poly(ADP-ribose) Polymerase Inhibitors - metabolism ; Poly(ADP-ribose) Polymerases - chemistry ; Poly(ADP-ribose) Polymerases - metabolism ; Rats ; Structure-Activity Relationship ; Xenograft Model Antitumor Assays</subject><ispartof>Journal of medicinal chemistry, 2020-12, Vol.63 (24), p.15541-15563</ispartof><rights>2020 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a348t-ae6bbcd6e07e4a60672b5a7af8ccd02da8046d18b966bdc214f184bfabed21cf3</citedby><cites>FETCH-LOGICAL-a348t-ae6bbcd6e07e4a60672b5a7af8ccd02da8046d18b966bdc214f184bfabed21cf3</cites><orcidid>0000-0001-5214-8291 ; 0000-0001-8792-9573</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.0c01346$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.0c01346$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2763,27074,27922,27923,56736,56786</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33264017$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Hexiang</creatorcontrib><creatorcontrib>Ren, Bo</creatorcontrib><creatorcontrib>Liu, Ye</creatorcontrib><creatorcontrib>Jiang, Beibei</creatorcontrib><creatorcontrib>Guo, Yin</creatorcontrib><creatorcontrib>Wei, Min</creatorcontrib><creatorcontrib>Luo, Lusong</creatorcontrib><creatorcontrib>Kuang, Xianzhao</creatorcontrib><creatorcontrib>Qiu, Ming</creatorcontrib><creatorcontrib>Lv, Lei</creatorcontrib><creatorcontrib>Xu, Hong</creatorcontrib><creatorcontrib>Qi, Ruipeng</creatorcontrib><creatorcontrib>Yan, Huibin</creatorcontrib><creatorcontrib>Xu, Dexu</creatorcontrib><creatorcontrib>Wang, Zhiwei</creatorcontrib><creatorcontrib>Huo, Chang-Xin</creatorcontrib><creatorcontrib>Zhu, Yutong</creatorcontrib><creatorcontrib>Zhao, Yuan</creatorcontrib><creatorcontrib>Wu, Yiyuan</creatorcontrib><creatorcontrib>Qin, Zhen</creatorcontrib><creatorcontrib>Su, Dan</creatorcontrib><creatorcontrib>Tang, Tristin</creatorcontrib><creatorcontrib>Wang, Fan</creatorcontrib><creatorcontrib>Sun, Xuebing</creatorcontrib><creatorcontrib>Feng, Yingcai</creatorcontrib><creatorcontrib>Peng, Hao</creatorcontrib><creatorcontrib>Wang, Xing</creatorcontrib><creatorcontrib>Gao, Yajuan</creatorcontrib><creatorcontrib>Liu, Yong</creatorcontrib><creatorcontrib>Gong, Wenfeng</creatorcontrib><creatorcontrib>Yu, Fenglong</creatorcontrib><creatorcontrib>Liu, Xuesong</creatorcontrib><creatorcontrib>Wang, Lai</creatorcontrib><creatorcontrib>Zhou, Changyou</creatorcontrib><title>Discovery of Pamiparib (BGB-290), a Potent and Selective Poly (ADP-ribose) Polymerase (PARP) Inhibitor in Clinical Development</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>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.</description><subject>Animals</subject><subject>Binding Sites</subject><subject>Carbazoles - chemistry</subject><subject>Carbazoles - metabolism</subject><subject>Carbazoles - pharmacology</subject><subject>Carbazoles - therapeutic use</subject><subject>Cell Proliferation - drug effects</subject><subject>Dogs</subject><subject>Female</subject><subject>Fluorenes - chemistry</subject><subject>Fluorenes - metabolism</subject><subject>Fluorenes - pharmacology</subject><subject>Fluorenes - therapeutic use</subject><subject>Half-Life</subject><subject>Humans</subject><subject>Indoles - chemistry</subject><subject>Indoles - metabolism</subject><subject>Indoles - pharmacology</subject><subject>Indoles - therapeutic use</subject><subject>Isoenzymes - antagonists & inhibitors</subject><subject>Isoenzymes - metabolism</subject><subject>Mice</subject><subject>Microsomes - metabolism</subject><subject>Molecular Docking Simulation</subject><subject>Neoplasms - drug therapy</subject><subject>Poly(ADP-ribose) Polymerase Inhibitors - chemistry</subject><subject>Poly(ADP-ribose) Polymerase Inhibitors - metabolism</subject><subject>Poly(ADP-ribose) Polymerases - chemistry</subject><subject>Poly(ADP-ribose) Polymerases - metabolism</subject><subject>Rats</subject><subject>Structure-Activity Relationship</subject><subject>Xenograft Model Antitumor Assays</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kEtLAzEUhYMotj7-gUiWLTj1JhMz47IPH4WCg4_1kGTu0Mi8SKaFbvztRqsuXV0495wD5yPkgsGEAWfXyvjJe42FWWM9AQMsFvKADNkNh0ikIA7JEIDziEseD8iJ9-8AEDMeH5NBHHMpgCVD8rGw3rRbdDvaljRTte2Us5qOZg-ziN_C-IoqmrU9Nj1VTUFfsELT2y0GsdrR0XSRRcHfehx_KzU65ZGOsulzNqbLZm217VtHbUPnlW2sURVd4BartqtD5xk5KlXl8fznnpK3-7vX-WO0enpYzqerSMUi7SOFUmtTSIQEhZIgE65vVKLK1JgCeKHCXlmwVN9KqQvDmShZKnSpNBacmTI-JWLfa1zrvcMy75ytldvlDPIvnHnAmf_izH9whtjlPtZtdPj9hX75BQPsDd_xduOasOL_zk-KuIRZ</recordid><startdate>20201224</startdate><enddate>20201224</enddate><creator>Wang, Hexiang</creator><creator>Ren, Bo</creator><creator>Liu, Ye</creator><creator>Jiang, Beibei</creator><creator>Guo, Yin</creator><creator>Wei, Min</creator><creator>Luo, Lusong</creator><creator>Kuang, Xianzhao</creator><creator>Qiu, Ming</creator><creator>Lv, Lei</creator><creator>Xu, Hong</creator><creator>Qi, Ruipeng</creator><creator>Yan, Huibin</creator><creator>Xu, Dexu</creator><creator>Wang, Zhiwei</creator><creator>Huo, Chang-Xin</creator><creator>Zhu, Yutong</creator><creator>Zhao, Yuan</creator><creator>Wu, Yiyuan</creator><creator>Qin, Zhen</creator><creator>Su, Dan</creator><creator>Tang, Tristin</creator><creator>Wang, Fan</creator><creator>Sun, Xuebing</creator><creator>Feng, Yingcai</creator><creator>Peng, Hao</creator><creator>Wang, Xing</creator><creator>Gao, Yajuan</creator><creator>Liu, Yong</creator><creator>Gong, Wenfeng</creator><creator>Yu, Fenglong</creator><creator>Liu, Xuesong</creator><creator>Wang, Lai</creator><creator>Zhou, Changyou</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><orcidid>https://orcid.org/0000-0001-5214-8291</orcidid><orcidid>https://orcid.org/0000-0001-8792-9573</orcidid></search><sort><creationdate>20201224</creationdate><title>Discovery of Pamiparib (BGB-290), a Potent and Selective Poly (ADP-ribose) Polymerase (PARP) Inhibitor in Clinical Development</title><author>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</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a348t-ae6bbcd6e07e4a60672b5a7af8ccd02da8046d18b966bdc214f184bfabed21cf3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Animals</topic><topic>Binding Sites</topic><topic>Carbazoles - chemistry</topic><topic>Carbazoles - metabolism</topic><topic>Carbazoles - pharmacology</topic><topic>Carbazoles - therapeutic use</topic><topic>Cell Proliferation - drug effects</topic><topic>Dogs</topic><topic>Female</topic><topic>Fluorenes - chemistry</topic><topic>Fluorenes - metabolism</topic><topic>Fluorenes - pharmacology</topic><topic>Fluorenes - therapeutic use</topic><topic>Half-Life</topic><topic>Humans</topic><topic>Indoles - chemistry</topic><topic>Indoles - metabolism</topic><topic>Indoles - pharmacology</topic><topic>Indoles - therapeutic use</topic><topic>Isoenzymes - antagonists & inhibitors</topic><topic>Isoenzymes - metabolism</topic><topic>Mice</topic><topic>Microsomes - metabolism</topic><topic>Molecular Docking Simulation</topic><topic>Neoplasms - drug therapy</topic><topic>Poly(ADP-ribose) Polymerase Inhibitors - chemistry</topic><topic>Poly(ADP-ribose) Polymerase Inhibitors - metabolism</topic><topic>Poly(ADP-ribose) Polymerases - chemistry</topic><topic>Poly(ADP-ribose) Polymerases - metabolism</topic><topic>Rats</topic><topic>Structure-Activity Relationship</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Hexiang</creatorcontrib><creatorcontrib>Ren, Bo</creatorcontrib><creatorcontrib>Liu, Ye</creatorcontrib><creatorcontrib>Jiang, Beibei</creatorcontrib><creatorcontrib>Guo, Yin</creatorcontrib><creatorcontrib>Wei, Min</creatorcontrib><creatorcontrib>Luo, Lusong</creatorcontrib><creatorcontrib>Kuang, Xianzhao</creatorcontrib><creatorcontrib>Qiu, Ming</creatorcontrib><creatorcontrib>Lv, Lei</creatorcontrib><creatorcontrib>Xu, Hong</creatorcontrib><creatorcontrib>Qi, Ruipeng</creatorcontrib><creatorcontrib>Yan, Huibin</creatorcontrib><creatorcontrib>Xu, Dexu</creatorcontrib><creatorcontrib>Wang, Zhiwei</creatorcontrib><creatorcontrib>Huo, Chang-Xin</creatorcontrib><creatorcontrib>Zhu, Yutong</creatorcontrib><creatorcontrib>Zhao, Yuan</creatorcontrib><creatorcontrib>Wu, Yiyuan</creatorcontrib><creatorcontrib>Qin, Zhen</creatorcontrib><creatorcontrib>Su, Dan</creatorcontrib><creatorcontrib>Tang, Tristin</creatorcontrib><creatorcontrib>Wang, Fan</creatorcontrib><creatorcontrib>Sun, Xuebing</creatorcontrib><creatorcontrib>Feng, Yingcai</creatorcontrib><creatorcontrib>Peng, Hao</creatorcontrib><creatorcontrib>Wang, Xing</creatorcontrib><creatorcontrib>Gao, Yajuan</creatorcontrib><creatorcontrib>Liu, Yong</creatorcontrib><creatorcontrib>Gong, Wenfeng</creatorcontrib><creatorcontrib>Yu, Fenglong</creatorcontrib><creatorcontrib>Liu, Xuesong</creatorcontrib><creatorcontrib>Wang, Lai</creatorcontrib><creatorcontrib>Zhou, Changyou</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Hexiang</au><au>Ren, Bo</au><au>Liu, Ye</au><au>Jiang, Beibei</au><au>Guo, Yin</au><au>Wei, Min</au><au>Luo, Lusong</au><au>Kuang, Xianzhao</au><au>Qiu, Ming</au><au>Lv, Lei</au><au>Xu, Hong</au><au>Qi, Ruipeng</au><au>Yan, Huibin</au><au>Xu, Dexu</au><au>Wang, Zhiwei</au><au>Huo, Chang-Xin</au><au>Zhu, Yutong</au><au>Zhao, Yuan</au><au>Wu, Yiyuan</au><au>Qin, Zhen</au><au>Su, Dan</au><au>Tang, Tristin</au><au>Wang, Fan</au><au>Sun, Xuebing</au><au>Feng, Yingcai</au><au>Peng, Hao</au><au>Wang, Xing</au><au>Gao, Yajuan</au><au>Liu, Yong</au><au>Gong, Wenfeng</au><au>Yu, Fenglong</au><au>Liu, Xuesong</au><au>Wang, Lai</au><au>Zhou, Changyou</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of Pamiparib (BGB-290), a Potent and Selective Poly (ADP-ribose) Polymerase (PARP) Inhibitor in Clinical Development</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2020-12-24</date><risdate>2020</risdate><volume>63</volume><issue>24</issue><spage>15541</spage><epage>15563</epage><pages>15541-15563</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><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.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>33264017</pmid><doi>10.1021/acs.jmedchem.0c01346</doi><tpages>23</tpages><orcidid>https://orcid.org/0000-0001-5214-8291</orcidid><orcidid>https://orcid.org/0000-0001-8792-9573</orcidid></addata></record> |
| fulltext | fulltext |
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| ispartof | Journal of medicinal chemistry, 2020-12, Vol.63 (24), p.15541-15563 |
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| source | MEDLINE; ACS Publications |
| subjects | Animals Binding Sites Carbazoles - chemistry Carbazoles - metabolism Carbazoles - pharmacology Carbazoles - therapeutic use Cell Proliferation - drug effects Dogs Female Fluorenes - chemistry Fluorenes - metabolism Fluorenes - pharmacology Fluorenes - therapeutic use Half-Life Humans Indoles - chemistry Indoles - metabolism Indoles - pharmacology Indoles - therapeutic use Isoenzymes - antagonists & inhibitors Isoenzymes - metabolism Mice Microsomes - metabolism Molecular Docking Simulation Neoplasms - drug therapy Poly(ADP-ribose) Polymerase Inhibitors - chemistry Poly(ADP-ribose) Polymerase Inhibitors - metabolism Poly(ADP-ribose) Polymerases - chemistry Poly(ADP-ribose) Polymerases - metabolism Rats Structure-Activity Relationship Xenograft Model Antitumor Assays |
| title | Discovery of Pamiparib (BGB-290), a Potent and Selective Poly (ADP-ribose) Polymerase (PARP) Inhibitor in Clinical Development |
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