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Article: Design and optimization of (3-aryl-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-ones as potent PLK4 inhibitors with oral antitumor efficacy

TitleDesign and optimization of (3-aryl-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-ones as potent PLK4 inhibitors with oral antitumor efficacy
Authors
Keywords(1H-Indazol-6-yl)-methylene)indolin-2-ones
Polo-like kinase 4
Antitumor agent
PLK4 inhibitors
Spiro[cyclopropane-1,3′-indolin]-2′-ones
Issue Date2016
Citation
Bioorganic and Medicinal Chemistry Letters, 2016, v. 26, n. 19, p. 4625-4630 How to Cite?
Abstract© 2016 Elsevier Ltd Previous efforts from our laboratory demonstrated that (E)-3-((3-(E)-vinylaryl)-1H-indazol-6-yl)methylene)-indolin-2-ones are potent PLK4 inhibitors with in vivo anticancer efficacy upon IP dosing. As part of a continued effort to develop selective and orally efficacious inhibitors, we examined variations on this theme wherein ‘directly-linked’ aromatics, pendant from the indazole core, replace the arylvinyl moiety. Herein, we describe the design and optimization of this series which was ultimately superseded by (3-aryl-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-ones. The latter compounds are potent and selective inhibitors of PLK4 with oral exposure in rodents and in vivo anticancer activity. Compound 13b, in particular, has a bioavailability of 22% and achieved a 96% tumor growth inhibition in an MDA-MB-468 xenograft study.
Persistent Identifierhttp://hdl.handle.net/10722/292962
ISSN
2023 Impact Factor: 2.5
2023 SCImago Journal Rankings: 0.508
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLi, Sze Wan-
dc.contributor.authorLiu, Yong-
dc.contributor.authorSampson, Peter B.-
dc.contributor.authorPatel, Narendra Kumar-
dc.contributor.authorForrest, Bryan T.-
dc.contributor.authorEdwards, Louise-
dc.contributor.authorLaufer, Radoslaw-
dc.contributor.authorFeher, Miklos-
dc.contributor.authorBan, Fuqiang-
dc.contributor.authorAwrey, Donald E.-
dc.contributor.authorHodgson, Richard-
dc.contributor.authorBeletskaya, Irina-
dc.contributor.authorMao, Guodong-
dc.contributor.authorMason, Jacqueline M.-
dc.contributor.authorWei, Xin-
dc.contributor.authorLuo, Xunyi-
dc.contributor.authorKiarash, Reza-
dc.contributor.authorGreen, Erin-
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.issued2016-
dc.identifier.citationBioorganic and Medicinal Chemistry Letters, 2016, v. 26, n. 19, p. 4625-4630-
dc.identifier.issn0960-894X-
dc.identifier.urihttp://hdl.handle.net/10722/292962-
dc.description.abstract© 2016 Elsevier Ltd Previous efforts from our laboratory demonstrated that (E)-3-((3-(E)-vinylaryl)-1H-indazol-6-yl)methylene)-indolin-2-ones are potent PLK4 inhibitors with in vivo anticancer efficacy upon IP dosing. As part of a continued effort to develop selective and orally efficacious inhibitors, we examined variations on this theme wherein ‘directly-linked’ aromatics, pendant from the indazole core, replace the arylvinyl moiety. Herein, we describe the design and optimization of this series which was ultimately superseded by (3-aryl-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-ones. The latter compounds are potent and selective inhibitors of PLK4 with oral exposure in rodents and in vivo anticancer activity. Compound 13b, in particular, has a bioavailability of 22% and achieved a 96% tumor growth inhibition in an MDA-MB-468 xenograft study.-
dc.languageeng-
dc.relation.ispartofBioorganic and Medicinal Chemistry Letters-
dc.subject(1H-Indazol-6-yl)-methylene)indolin-2-ones-
dc.subjectPolo-like kinase 4-
dc.subjectAntitumor agent-
dc.subjectPLK4 inhibitors-
dc.subjectSpiro[cyclopropane-1,3′-indolin]-2′-ones-
dc.titleDesign and optimization of (3-aryl-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-ones as potent PLK4 inhibitors with oral antitumor efficacy-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.bmcl.2016.08.063-
dc.identifier.pmid27592744-
dc.identifier.scopuseid_2-s2.0-84985918718-
dc.identifier.volume26-
dc.identifier.issue19-
dc.identifier.spage4625-
dc.identifier.epage4630-
dc.identifier.eissn1464-3405-
dc.identifier.isiWOS:000383359400013-
dc.identifier.issnl0960-894X-

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