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Article: The discovery of polo-like kinase 4 inhibitors: Design and optimization of spiro[cyclopropane-1,3′[3H]indol]-2′(1′H).ones as orally bioavailable antitumor agents

TitleThe discovery of polo-like kinase 4 inhibitors: Design and optimization of spiro[cyclopropane-1,3′[3H]indol]-2′(1′H).ones as orally bioavailable antitumor agents
Authors
Issue Date2015
Citation
Journal of Medicinal Chemistry, 2015, v. 58, n. 1, p. 130-146 How to Cite?
Abstract© 2014 American Chemical Society. Polo-like kinase 4 (PLK4), a unique member of the polo-like kinase family of serine-threonine kinases, is a master regulator of centriole duplication that is important for maintaining genome integrity. Overexpression of PLK4 is found in several human cancers and is linked with a predisposition to tumorigenesis. Previous efforts to identify potent and efficacious PLK4 inhibitors resulted in the discovery of (E)-3-((1H-indazol-6-yl)methylene)indolin-2-ones, which are superseded by the bioisosteric 2-(1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-ones reported herein. Optimization of this new cyclopropane-linked series was based on a computational model of a PLK4 X-ray structure and SAR attained from the analogous alkenelinked series. The racemic cyclopropane-linked compounds showed PLK4 affinity and antiproliferative activity comparable to their alkene-linked congeners with improved physicochemical, ADME, and pharmacokinetic properties. Positive xenograft results from the MDA-MB-468 human breast cancer xenograft model for compound 18 support the investigation of PLK4 inhibitors as anticancer therapeutics. A PLK4 X-ray co-structure with racemate 18 revealed preferential binding of the 1R,2S enantiomer to the PLK4 kinase domain.
Persistent Identifierhttp://hdl.handle.net/10722/292961
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.authorPatel, Narendra Kumar-
dc.contributor.authorFeher, Miklos-
dc.contributor.authorForrest, Bryan-
dc.contributor.authorLi, Sze Wan-
dc.contributor.authorEdwards, Louise-
dc.contributor.authorLaufer, Radoslaw-
dc.contributor.authorLang, Yunhui-
dc.contributor.authorBan, Fuqiang-
dc.contributor.authorAwrey, Donald E.-
dc.contributor.authorMao, Guodong-
dc.contributor.authorPlotnikova, Olga-
dc.contributor.authorLeung, Genie-
dc.contributor.authorHodgson, Richard-
dc.contributor.authorMason, Jacqueline-
dc.contributor.authorWei, Xin-
dc.contributor.authorKiarash, Reza-
dc.contributor.authorGreen, Erin-
dc.contributor.authorQiu, Wei-
dc.contributor.authorChirgadze, Nickolay Y.-
dc.contributor.authorMak, Tak W.-
dc.contributor.authorPan, Guohua-
dc.contributor.authorPauls, Henry W.-
dc.date.accessioned2020-11-17T14:57:35Z-
dc.date.available2020-11-17T14:57:35Z-
dc.date.issued2015-
dc.identifier.citationJournal of Medicinal Chemistry, 2015, v. 58, n. 1, p. 130-146-
dc.identifier.issn0022-2623-
dc.identifier.urihttp://hdl.handle.net/10722/292961-
dc.description.abstract© 2014 American Chemical Society. Polo-like kinase 4 (PLK4), a unique member of the polo-like kinase family of serine-threonine kinases, is a master regulator of centriole duplication that is important for maintaining genome integrity. Overexpression of PLK4 is found in several human cancers and is linked with a predisposition to tumorigenesis. Previous efforts to identify potent and efficacious PLK4 inhibitors resulted in the discovery of (E)-3-((1H-indazol-6-yl)methylene)indolin-2-ones, which are superseded by the bioisosteric 2-(1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-ones reported herein. Optimization of this new cyclopropane-linked series was based on a computational model of a PLK4 X-ray structure and SAR attained from the analogous alkenelinked series. The racemic cyclopropane-linked compounds showed PLK4 affinity and antiproliferative activity comparable to their alkene-linked congeners with improved physicochemical, ADME, and pharmacokinetic properties. Positive xenograft results from the MDA-MB-468 human breast cancer xenograft model for compound 18 support the investigation of PLK4 inhibitors as anticancer therapeutics. A PLK4 X-ray co-structure with racemate 18 revealed preferential binding of the 1R,2S enantiomer to the PLK4 kinase domain.-
dc.languageeng-
dc.relation.ispartofJournal of Medicinal Chemistry-
dc.titleThe discovery of polo-like kinase 4 inhibitors: Design and optimization of spiro[cyclopropane-1,3′[3H]indol]-2′(1′H).ones as orally bioavailable antitumor agents-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1021/jm500537u-
dc.identifier.pmid24867403-
dc.identifier.scopuseid_2-s2.0-84984910848-
dc.identifier.volume58-
dc.identifier.issue1-
dc.identifier.spage130-
dc.identifier.epage146-
dc.identifier.eissn1520-4804-
dc.identifier.isiWOS:000347743700008-
dc.identifier.issnl0022-2623-

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