X‑ray Crystallography-Guided Design, Antitumor Efficacy, and QSAR Analysis of Metabolically Stable Cyclopenta-Pyrimidinyl Dihydroquinoxalinone as a Potent Tubulin Polymerization Inhibitor
Small molecules that interact with the colchicine binding site in tubulin have demonstrated therapeutic efficacy in treating cancers. We report the design, syntheses, and antitumor efficacies of new analogues of pyridopyrimidine and hydroquinoxalinone compounds with improved drug-like characteristic...
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| Veröffentlicht in: | Journal of medicinal chemistry 2021-09, Vol.64 (17), p.13072-13095 |
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| creator | Banerjee, Souvik Mahmud, Foyez Deng, Shanshan Ma, Lingling Yun, Mi-Kyung Fakayode, Sayo O Arnst, Kinsie E Yang, Lei Chen, Hao Wu, Zhongzhi Lukka, Pradeep B Parmar, Keyur Meibohm, Bernd White, Stephen W Wang, Yuxi Li, Wei Miller, Duane D |
| description | Small molecules that interact with the colchicine binding site in tubulin have demonstrated therapeutic efficacy in treating cancers. We report the design, syntheses, and antitumor efficacies of new analogues of pyridopyrimidine and hydroquinoxalinone compounds with improved drug-like characteristics. Eight analogues, 5j, 5k, 5l, 5m, 5n, 5r, 5t, and 5u, showed significant improvement in metabolic stability and demonstrated strong antiproliferative potency in a panel of human cancer cell lines, including melanoma, lung cancer, and breast cancer. We report crystal structures of tubulin in complex with five representative compounds, 5j, 5k, 5l, 5m, and 5t, providing direct confirmation for their binding to the colchicine site in tubulin. A quantitative structure–activity relationship analysis of the synthesized analogues showed strong ability to predict potency. In vivo, 5m (4 mg/kg) and 5t (5 mg/kg) significantly inhibited tumor growth as well as melanoma spontaneous metastasis into the lung and liver against a highly paclitaxel-resistant A375/TxR xenograft model. |
| doi_str_mv | 10.1021/acs.jmedchem.1c01202 |
| format | Article |
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We report the design, syntheses, and antitumor efficacies of new analogues of pyridopyrimidine and hydroquinoxalinone compounds with improved drug-like characteristics. Eight analogues, 5j, 5k, 5l, 5m, 5n, 5r, 5t, and 5u, showed significant improvement in metabolic stability and demonstrated strong antiproliferative potency in a panel of human cancer cell lines, including melanoma, lung cancer, and breast cancer. We report crystal structures of tubulin in complex with five representative compounds, 5j, 5k, 5l, 5m, and 5t, providing direct confirmation for their binding to the colchicine site in tubulin. A quantitative structure–activity relationship analysis of the synthesized analogues showed strong ability to predict potency. In vivo, 5m (4 mg/kg) and 5t (5 mg/kg) significantly inhibited tumor growth as well as melanoma spontaneous metastasis into the lung and liver against a highly paclitaxel-resistant A375/TxR xenograft model.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.1c01202</identifier><identifier>PMID: 34406768</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Apoptosis - drug effects ; Cell Cycle - drug effects ; Cell Line, Tumor ; Cell Survival - drug effects ; Crystallography, X-Ray ; Drug Design ; Drug Resistance, Neoplasm ; Female ; Humans ; Male ; Mice ; Quantitative Structure-Activity Relationship ; Quinoxalines - chemistry ; Quinoxalines - pharmacology ; Tubulin Modulators - chemistry ; Tubulin Modulators - pharmacology ; Xenograft Model Antitumor Assays</subject><ispartof>Journal of medicinal chemistry, 2021-09, Vol.64 (17), p.13072-13095</ispartof><rights>2021 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a449t-d13c7acf3f4865225a7ef4ed4e4201c7037914ff0faa4878b1e3d79aa549a3a3</citedby><cites>FETCH-LOGICAL-a449t-d13c7acf3f4865225a7ef4ed4e4201c7037914ff0faa4878b1e3d79aa549a3a3</cites><orcidid>0000-0002-6093-0985 ; 0000-0002-4056-5829 ; 0000-0001-8034-7810 ; 0000-0003-3923-3648 ; 0000-0002-9522-4474 ; 0000-0002-7811-2577</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.1c01202$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.1c01202$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,314,776,780,881,2751,27055,27903,27904,56716,56766</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34406768$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Banerjee, Souvik</creatorcontrib><creatorcontrib>Mahmud, Foyez</creatorcontrib><creatorcontrib>Deng, Shanshan</creatorcontrib><creatorcontrib>Ma, Lingling</creatorcontrib><creatorcontrib>Yun, Mi-Kyung</creatorcontrib><creatorcontrib>Fakayode, Sayo O</creatorcontrib><creatorcontrib>Arnst, Kinsie E</creatorcontrib><creatorcontrib>Yang, Lei</creatorcontrib><creatorcontrib>Chen, Hao</creatorcontrib><creatorcontrib>Wu, Zhongzhi</creatorcontrib><creatorcontrib>Lukka, Pradeep B</creatorcontrib><creatorcontrib>Parmar, Keyur</creatorcontrib><creatorcontrib>Meibohm, Bernd</creatorcontrib><creatorcontrib>White, Stephen W</creatorcontrib><creatorcontrib>Wang, Yuxi</creatorcontrib><creatorcontrib>Li, Wei</creatorcontrib><creatorcontrib>Miller, Duane D</creatorcontrib><title>X‑ray Crystallography-Guided Design, Antitumor Efficacy, and QSAR Analysis of Metabolically Stable Cyclopenta-Pyrimidinyl Dihydroquinoxalinone as a Potent Tubulin Polymerization Inhibitor</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Small molecules that interact with the colchicine binding site in tubulin have demonstrated therapeutic efficacy in treating cancers. We report the design, syntheses, and antitumor efficacies of new analogues of pyridopyrimidine and hydroquinoxalinone compounds with improved drug-like characteristics. Eight analogues, 5j, 5k, 5l, 5m, 5n, 5r, 5t, and 5u, showed significant improvement in metabolic stability and demonstrated strong antiproliferative potency in a panel of human cancer cell lines, including melanoma, lung cancer, and breast cancer. We report crystal structures of tubulin in complex with five representative compounds, 5j, 5k, 5l, 5m, and 5t, providing direct confirmation for their binding to the colchicine site in tubulin. A quantitative structure–activity relationship analysis of the synthesized analogues showed strong ability to predict potency. 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Med. Chem</addtitle><date>2021-09-09</date><risdate>2021</risdate><volume>64</volume><issue>17</issue><spage>13072</spage><epage>13095</epage><pages>13072-13095</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Small molecules that interact with the colchicine binding site in tubulin have demonstrated therapeutic efficacy in treating cancers. We report the design, syntheses, and antitumor efficacies of new analogues of pyridopyrimidine and hydroquinoxalinone compounds with improved drug-like characteristics. Eight analogues, 5j, 5k, 5l, 5m, 5n, 5r, 5t, and 5u, showed significant improvement in metabolic stability and demonstrated strong antiproliferative potency in a panel of human cancer cell lines, including melanoma, lung cancer, and breast cancer. We report crystal structures of tubulin in complex with five representative compounds, 5j, 5k, 5l, 5m, and 5t, providing direct confirmation for their binding to the colchicine site in tubulin. A quantitative structure–activity relationship analysis of the synthesized analogues showed strong ability to predict potency. In vivo, 5m (4 mg/kg) and 5t (5 mg/kg) significantly inhibited tumor growth as well as melanoma spontaneous metastasis into the lung and liver against a highly paclitaxel-resistant A375/TxR xenograft model.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>34406768</pmid><doi>10.1021/acs.jmedchem.1c01202</doi><tpages>24</tpages><orcidid>https://orcid.org/0000-0002-6093-0985</orcidid><orcidid>https://orcid.org/0000-0002-4056-5829</orcidid><orcidid>https://orcid.org/0000-0001-8034-7810</orcidid><orcidid>https://orcid.org/0000-0003-3923-3648</orcidid><orcidid>https://orcid.org/0000-0002-9522-4474</orcidid><orcidid>https://orcid.org/0000-0002-7811-2577</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Apoptosis - drug effects Cell Cycle - drug effects Cell Line, Tumor Cell Survival - drug effects Crystallography, X-Ray Drug Design Drug Resistance, Neoplasm Female Humans Male Mice Quantitative Structure-Activity Relationship Quinoxalines - chemistry Quinoxalines - pharmacology Tubulin Modulators - chemistry Tubulin Modulators - pharmacology Xenograft Model Antitumor Assays |
| title | X‑ray Crystallography-Guided Design, Antitumor Efficacy, and QSAR Analysis of Metabolically Stable Cyclopenta-Pyrimidinyl Dihydroquinoxalinone as a Potent Tubulin Polymerization Inhibitor |
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