Abstract
The p53 tumor suppressor is controlled by MDM2, which binds p53 and negatively regulates its transcriptional activity and stability. Many tumors overproduce MDM2 to impair p53 function. Therefore, restoration of p53 activity by inhibiting the p53-MDM2 binding represents an attractive novel approach to cancer therapy. We previously reported the discovery AM-8553, a potent and selective piperidinone inhibitor of the MDM2-p53 interaction (Rew et al. J. Med. Chem. 2012, 55, 4936). We report here continued research on the N-alkyl substituent of this series, focused in particular on a previously underutilized interaction in a shallow cleft on the MDM2 surface that led to the discovery of variety of sulfonamides and sulfones which gave rise to substantial improvements in biochemical and cellular potency. Further work led to discovery of AMG 232, which is currently being evaluated in human clinical trials for the treatment of cancer. AMG 232 is an extremely potent MDM2 inhibitor (SPR KD = 0.045 nM, SJSA-1 EdU IC50 = 9.1 nM), with remarkable pharmacokinetic properties. The compound interacts specifically with the p53-binding pocket of MDM2 and releases the p53 protein from negative control. Treatment of cancer cells expressing wild-type p53 with AMG 232, stabilizes p53 and activates the p53 pathway, leading to cell cycle arrest and apoptosis. The compound showed excellent efficacy in a number of mouse tumor xenograft models and was well tolerated in preclinical toxicology studies at therapeutically relevant dosages.
Citation Format: Zhihong Li. Discovery of AMG 232, an inhibitor of the MDM2-p53 interaction: From lead to a clinical candidate. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1645. doi:10.1158/1538-7445.AM2014-1645
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