The tumor suppressor protein p53 plays a pivotal role in protecting cells from malignant transformation. It activates the transcription of numerous genes involved in cell cycle arrest, DNA repair, senescence, and apoptosis. Recent studies demonstrate that restoring endogenous p53 function causes tumor regression in vivo. 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. All of these mechanisms would be blocked by neutralizing the MDM2-p53 interaction. This therapeutic strategy could potentially be applied to the ~50% of tumors that are p53WT (~725,000 patients are diagnosed annually with p53WTtumors in the US alone).This presentation will describe a successful approach for designing new scaffolds of MDM2 inhibitors based on the binding mode of known inhibitors with MDM2 protein. Through a combination of X-ray crystallography, molecular modeling, and iterative medicinal chemistry, we have identified potent inhibitors of the MDM2-p53 interaction. The affinity of these compounds for MDM2 was improved through conformational control of both the piperidinone ring and the appended N-alkyl substituent.Our optimization efforts resulted in the discovery of AM-8553, a highly potent selective MDM2 inhibitor (Surface Plasmon Resonance Kd = 0.4 nM, SJSA-1 EdU cell proliferation IC50 = 72 nM), with excellent pharmacokinetic properties and in vivo anti-tumor activity inthe SJSA-1 osteosarcoma xenograft model.

Structure-based de novo design of novel inhibitors of the MDM2-p53 interaction

246th National Meeting (2013)

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