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ID: ALA4428091
Journal: Bioorg Med Chem Lett
Title: 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.
Authors: Li SW, Liu Y, Sampson PB, Patel NK, Forrest BT, Edwards L, Laufer R, Feher M, Ban F, Awrey DE, Hodgson R, Beletskaya I, Mao G, Mason JM, Wei X, Luo X, Kiarash R, Green E, Mak TW, Pan G, Pauls HW.
Abstract: 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 Herein, we describe the design and optimization of this series which was ultimately superseded by (3-aryl-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-ones.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.
CiteXplore: 27592744