Recognized as the �guardian of the genome� the transcription factor p53-protein is the cell's main tumor suppressor. Upon cellular stress, p53 triggers a lethal response by regulating the expression of multiple target genes that control cell cycle arrest, apoptosis, senescence and DNA repair. In about 50% of cancer cells, p53 inactivation takes place through mutations within the p53 gene (TR53) or by translational modifications of its gene product. In those tumors that retain wild-type p53 function, loss of activity is achieved by other means such as direct inhibition by its natural agonists. The oncogene MDM2-protein has been identified as p53's main antagonist. As a result, disruption of this MDM2-p53 protein-protein interaction emerged an attractive strategy for the activation of the p53 pathway. To date, several small molecule inhibitors of the MDM2-p53 interaction have been tested in the clinic for the treatment of cancer.The title presentation will describe our continued quest towards finding new inhibitor scaffolds. These efforts lead to the discovery of a new class of morpholinone MDM2 inhibitors. Among these, (1)  is a highly potent inhibitor (EdU IC50 = 22 nM), with remarkable pharmacokinetic properties and in vivo anti-tumor activity in the SJSA-1 osteosarcoma xenograft model (ED50 = 41 mg/kg). In addition, we will discuss the important differences in potency and divergent metabolism pathways observed between this new class of morpholinone inhibitors and their previously reported piperidinone counterparts. 

Selective and potent morpholinone inhibitors of the MDM2-p53 interaction

246th National Meeting (2013)

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