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Article: The discovery of polo-like kinase 4 inhibitors: Identification of (1 R,2 S)-2-(3-((E)-4-(((cis)-2,6-Dimethylmorpholino)methyl)styryl)-1 H -indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one (CFI-400945) as a potent, orally active antitumor agent

TitleThe discovery of polo-like kinase 4 inhibitors: Identification of (1 R,2 S)-2-(3-((E)-4-(((cis)-2,6-Dimethylmorpholino)methyl)styryl)-1 H -indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one (CFI-400945) as a potent, orally active antitumor agent
Authors
Issue Date2015
Citation
Journal of Medicinal Chemistry, 2015, v. 58, n. 1, p. 147-169 How to Cite?
Abstract© 2014 American Chemical Society. Previous publications from our laboratory have introduced novel inhibitors of Polo-like kinase 4 (PLK4), a mitotic kinase identified as a potential target for cancer therapy. The search for potent and selective PLK4 inhibitors yielded (E)-3-((1H-indazol-6-yl)methylene)indolin-2-ones, which were superseded by the bioisosteric 2-(1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-ones, e.g., 3. The later scaffold confers improved drug-like properties and incorporates two stereogenic centers. This work reports the discovery of a novel one-pot double SN2 displacement reaction for the stereoselective installation of the desired asymmetric centers and confirms the stereochemistry of the most potent stereoisomer, e.g., 44. Subsequent work keys on the optimization of the oral exposure of nanomolar PLK4 inhibitors with potent cancer cell growth inhibitory activity. A short list of compounds with superior potency and pharmacokinetic properties in rodents and dogs was studied in mouse models of tumor growth. We conclude with the identification of compound 48 (designated CFI-400945) as a novel clinical candidate for cancer therapy.
Persistent Identifierhttp://hdl.handle.net/10722/292862
ISSN
2023 Impact Factor: 6.8
2023 SCImago Journal Rankings: 1.986
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorSampson, Peter B.-
dc.contributor.authorLiu, Yong-
dc.contributor.authorForrest, Bryan-
dc.contributor.authorCumming, Graham-
dc.contributor.authorLi, Sze Wan-
dc.contributor.authorPatel, Narendra Kumar-
dc.contributor.authorEdwards, Louise-
dc.contributor.authorLaufer, Radoslaw-
dc.contributor.authorFeher, Miklos-
dc.contributor.authorBan, Fuqiang-
dc.contributor.authorAwrey, Donald E.-
dc.contributor.authorMao, Guodong-
dc.contributor.authorPlotnikova, Olga-
dc.contributor.authorHodgson, Richard-
dc.contributor.authorBeletskaya, Irina-
dc.contributor.authorMason, Jacqueline M.-
dc.contributor.authorLuo, Xunyi-
dc.contributor.authorNadeem, Vincent-
dc.contributor.authorWei, Xin-
dc.contributor.authorKiarash, Reza-
dc.contributor.authorMadeira, Brian-
dc.contributor.authorHuang, Ping-
dc.contributor.authorMak, Tak W.-
dc.contributor.authorPan, Guohua-
dc.contributor.authorPauls, Henry W.-
dc.date.accessioned2020-11-17T14:57:22Z-
dc.date.available2020-11-17T14:57:22Z-
dc.date.issued2015-
dc.identifier.citationJournal of Medicinal Chemistry, 2015, v. 58, n. 1, p. 147-169-
dc.identifier.issn0022-2623-
dc.identifier.urihttp://hdl.handle.net/10722/292862-
dc.description.abstract© 2014 American Chemical Society. Previous publications from our laboratory have introduced novel inhibitors of Polo-like kinase 4 (PLK4), a mitotic kinase identified as a potential target for cancer therapy. The search for potent and selective PLK4 inhibitors yielded (E)-3-((1H-indazol-6-yl)methylene)indolin-2-ones, which were superseded by the bioisosteric 2-(1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-ones, e.g., 3. The later scaffold confers improved drug-like properties and incorporates two stereogenic centers. This work reports the discovery of a novel one-pot double S<inf>N</inf>2 displacement reaction for the stereoselective installation of the desired asymmetric centers and confirms the stereochemistry of the most potent stereoisomer, e.g., 44. Subsequent work keys on the optimization of the oral exposure of nanomolar PLK4 inhibitors with potent cancer cell growth inhibitory activity. A short list of compounds with superior potency and pharmacokinetic properties in rodents and dogs was studied in mouse models of tumor growth. We conclude with the identification of compound 48 (designated CFI-400945) as a novel clinical candidate for cancer therapy.-
dc.languageeng-
dc.relation.ispartofJournal of Medicinal Chemistry-
dc.titleThe discovery of polo-like kinase 4 inhibitors: Identification of (1 R,2 S)-2-(3-((E)-4-(((cis)-2,6-Dimethylmorpholino)methyl)styryl)-1 H -indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one (CFI-400945) as a potent, orally active antitumor agent-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1021/jm5005336-
dc.identifier.pmid25723005-
dc.identifier.scopuseid_2-s2.0-84920814085-
dc.identifier.volume58-
dc.identifier.issue1-
dc.identifier.spage147-
dc.identifier.epage169-
dc.identifier.eissn1520-4804-
dc.identifier.isiWOS:000347743700009-
dc.identifier.issnl0022-2623-

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