Novel inhibitors of the MDM2-p53 interaction featuring hydrogen bond acceptors as carboxylic acid isosteres

J Med Chem. 2014 Apr 10;57(7):2963-88. doi: 10.1021/jm401911v. Epub 2014 Mar 27.

Abstract

We previously reported the discovery of potent and selective morpholinone and piperidinone inhibitors of the MDM2-p53 interaction. These inhibitors have in common a carboxylic acid moiety that engages in an electrostatic interaction with MDM2-His96. Our continued search for potent and diverse inhibitors led to the discovery of novel replacements for these acids uncovering new interactions with the MDM2 protein. In particular, using pyridine or thiazole as isosteres of the carboxylic acid moiety resulted in very potent analogues. From these, AM-6761 (4) emerged as a potent inhibitor with remarkable biochemical (HTRF IC50 = 0.1 nM) and cellular potency (SJSA-1 EdU IC50 = 16 nM), as well as favorable pharmacokinetic properties. Compound 4 also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 11 mg/kg. Optimization efforts toward the discovery of these inhibitors as well as the new interactions observed with the MDM2 protein are described herein.

MeSH terms

  • Acetates / chemistry
  • Acetates / pharmacology*
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Bone Neoplasms / drug therapy
  • Carboxylic Acids / chemistry
  • Carboxylic Acids / pharmacology*
  • Cell Proliferation / drug effects*
  • Cells, Cultured
  • Crystallography, X-Ray
  • Drug Design
  • Female
  • Humans
  • Hydrogen Bonding
  • Mice
  • Mice, Nude
  • Models, Molecular
  • Molecular Structure
  • Myocytes, Smooth Muscle / drug effects*
  • Osteosarcoma / drug therapy
  • Piperidones / chemistry
  • Piperidones / pharmacology*
  • Protein Binding
  • Protein Interaction Domains and Motifs / drug effects*
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / antagonists & inhibitors*
  • Tumor Suppressor Protein p53 / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • 2-(2-(1-(2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-chloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)methyl)thiazol-5-yl)acetic acid
  • Acetates
  • Antineoplastic Agents
  • Carboxylic Acids
  • Piperidones
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2

Associated data

  • PDB/4OCC
  • PDB/4ODE
  • PDB/4ODF
  • PDB/4OGN
  • PDB/4OGT
  • PDB/4OGV