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. Issue 19 (1st October 2016)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 19(2016)
• Page Start: 4625
• Page End: 4630
• Publication Date: 2016-10-01
• Subjects: Polo-like kinase 4 -- PLK4 inhibitors -- Spiro[cyclopropane-1, 3′-indolin]-2′-ones -- (1H-Indazol-6-yl)-methylene)indolin-2-ones -- Antitumor agent; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.08.063
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Previous efforts from our laboratory demonstrated that ( E )-3-((3-( E )-vinylaryl)-1 H -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 Herein, we describe the design and optimization of this series which was ultimately superseded by (3-aryl-1 H -indazol-6-yl)spiro[cyclopropane-1, 3′-indolin]-2′-ones.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. Compound13b, in particular, has a bioavailability of 22% and achieved a 96% tumor growth inhibition in an MDA-MB-468 xenograft study.