Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 26, Issue 19, Pages 4625-4630Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2016.08.063
Keywords
Polo-like kinase 4; PLK4 inhibitors; Spiro[cyclopropane-1,3 '-indolin]-2 '-ones; (1H-Indazol-6-yl)-methylene)indolin-2-ones; Antitumor agent
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Funding
- Princess Margaret Cancer Foundation
- Canadian Institute of Health Research
- Canadian Foundation for Innovation
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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 Herein, we describe the design and optimization of this series which was ultimately superseded by (3-aryl-1H-indazol-6-yl) spiro[cyclopropane-1,30-indolin]-20-ones.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. (C) 2016 Elsevier Ltd. All rights reserved.
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