The tumor suppressor protein p53 plays a central role in preventing tumor development by upregulating the transcription of numerous genes involved in cell cycle arrest and apoptosis. Inactivation of the p53 pathway in tumor cells provides a strong selective growth advantage, and it has been proposed that elimination of p53 function may be a requisite step in tumor formation.The MDM2 (murine double minute 2) oncogene is an important negative regulator of p53. MDM2 is transcriptionally activated by p53, and the activity of p53 is regulated by MDM2 through various mechanisms. Wild-type p53 is found in approximately 50% of human cancers, and inhibition of the MDM2-p53 interaction with small-molecule MDM2 inhibitors has been shown to be a tractable mechanism for the activation of the endogenous p53 pathway and the treatment of a variety of wild type p53 tumors.This presentation will describe the structure-based rational design of novel MDM2 inhibitors, which led to the discovery of a series of 1,3,5,6-tetrasubstituted piperidinone derivatives. The affinity of these compounds for MDM2 was improved through conformational control of both the piperidinone ring and the appended N-alkyl substituent.Further optimization resulted in the discovery of AM-8553 which demonstrated high in vitro potency (KD = 0.4 nM) and significant anti-tumor efficacy in SJSA-1 xenograft studies. AM-8553 is a highly selective and orally bioavailable inhibitor of the MDM2-p53 interaction. In addition, AM-8553 is projected to have low clearance and a long half-life in humans. Figure 1. <img src='https://acs-archive-assets2.s3.amazonaws.com/240nm/uploads/41137_fig.1_lysozyme-nag3.jpg' alt='' />

Discovery of AM-8553: Structure-based design of novel piperidinone inhibitors of the MDM2-p53 interaction

244th National Meeting (2012)

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