Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 56, Issue 13, Pages 5553-5561Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm4005708
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Funding
- National Cancer Institute, National Institutes of Health [R01CA121279, P50CA06956, P50CA097248]
- University of Michigan Cancer Center [P30CA046592]
- Ascenta Therapeutics, Inc.
- Sanofi S.A
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We previously reported the discovery of a class of spirooxindoles as potent and selective small-molecule inhibitors of the MDM2-p53 interaction (MDM2 inhibitors). We report herein our efforts to improve their pharmacokinetic properties and in vivo antitumor activity. Our efforts led to the identification of 9 (MI-888) as a potent, MDM2 inhibitor (K-i = 0.44 nM) with a superior pharmacokinetic profile and enhanced in vivo efficacy. Compound 9 is capable of achieving rapid, of human cancer with oral administration and represents the most potent complete, and durable tumor regression in two types xenograft models and efficacious MDM2 inhibitor reported to date.
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