201. Design and optimization of (3-aryl-1 H -indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-ones as potent PLK4 inhibitors with oral antitumor efficacy
- Author
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Henry W. Pauls, Peter Brent Sampson, Guodong Mao, Irina Beletskaya, Guohua Pan, Tak W. Mak, Yong Liu, Bryan T. Forrest, Sze-Wan Li, Narendra Kumar B. Patel, Xin Wei, Miklos Feher, Richard J. Hodgson, Jacqueline M. Mason, Erin Green, Reza Kiarash, Louise Edwards, Radoslaw Laufer, Xunyi Luo, Fuqiang Ban, and Donald E. Awrey
- Subjects
0301 basic medicine ,Indoles ,Stereochemistry ,Clinical Biochemistry ,Administration, Oral ,Pharmaceutical Science ,Antineoplastic Agents ,Protein Serine-Threonine Kinases ,01 natural sciences ,Biochemistry ,Cyclopropane ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,In vivo ,Cell Line, Tumor ,Drug Discovery ,Animals ,Humans ,Moiety ,Protein Kinase Inhibitors ,Molecular Biology ,Antitumor activity ,Indazole ,010405 organic chemistry ,Aryl ,Organic Chemistry ,Rats ,3. Good health ,0104 chemical sciences ,Bioavailability ,030104 developmental biology ,chemistry ,Area Under Curve ,Drug Design ,Heterografts ,Molecular Medicine ,Tumor growth inhibition - 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 Herein, we describe the design and optimization of this series which was ultimately superseded by (3-aryl-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-ones.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.
- Published
- 2016