1247003-79-7Relevant academic research and scientific papers
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
Li, Sze-Wan,Liu, Yong,Sampson, Peter B.,Patel, Narendra Kumar,Forrest, Bryan T.,Edwards, Louise,Laufer, Radoslaw,Feher, Miklos,Ban, Fuqiang,Awrey, Donald E.,Hodgson, Richard,Beletskaya, Irina,Mao, Guodong,Mason, Jacqueline M.,Wei, Xin,Luo, Xunyi,Kiarash, Reza,Green, Erin,Mak, Tak W.,Pan, Guohua,Pauls, Henry W.
, p. 4625 - 4630 (2016/09/13)
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 Herein, we describe the design and optimization of this series which was ultimately superseded by (3-aryl-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-ones.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.
