Activation of the pro-apoptotic protein p53 is a promising approach towards the treatment of cancer. p53 activation leads to the transcription of multiple downstream genes that regulate cell cycle control, apoptosis, DNA repair and senescence. About half of all human cancers progress either by mutation or deletion of p53. However, for the half that retains p53wt activity, survival is achieved by other mechanisms such as upregulation of one of its natural antagonists, MDM2. We and others aimed to design small molecules that bind to MDM2 impeding it's interaction with p53, reactivating its pathways. From these, several inhibitors have emerged and are now being tested in the clinic. We recently reported the discovery of potent and selective morpholinone and piperidinone inhibitors of the MDM2-p53 interaction, including our clinical candidate AMG 232. These inhibitors have in common a carboxylic acid moiety that engages in an electrostatic interaction with MDM2-His96. This presentation discusses our continued search for diverse inhibitors leading to the discovery of novel replacements for these acids and uncovering new interactions with the MDM2 protein. In particular, using pyridine or thiazole as carboxylic acid isosteres resulted in very potent analogues. For example, piperidinone-thiazole AM-6761 has remarkable biochemical (HTRF IC50 = 0.1 nM) and cellular potency (SJSA-1 EdU IC50 = 16 nM), favorable pharmacokinetic properties and excellent anti-tumor activity in vivo in the SJSA-1 osteosarcoma mouse xenograft model with an ED50 of 11 mg/kg. Optimization efforts towards the discovery of these inhibitors as well as the difference in clearance pathways between AM-6761 and AMG 232 will be discussed.

Novel inhibitors of the MDM2-p53 interaction featuring carboxylic acid isosteres

248th National Meeting (2014)

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