Phe19 modification of HDM2-p53 PPI inhibitors to alleviate CYP3A4 metabolism/mechanism-based inhibition liability

Bioorg Med Chem Lett. 2022 Apr 1:61:128625. doi: 10.1016/j.bmcl.2022.128625. Epub 2022 Feb 11.

Abstract

The discovery of potent, bioavailable small molecule inhibitors of p53-HDM2 PPI led us to investigate subsequent modifications to address a CYP3A4 time-dependent inhibition liability. On the basis of the crystal structure of HDM2 in complex with 2, further functionalization of the solvent exposed area of the molecule that binds to Phe19 pocket were investigated as a strategy to modulate the molecule liphophilicity. Introduction of 2-oxo-nicotinic amide at Phe19 proved a viable strategy in obtaining inhibitors exempt from CYP3A4 time-dependent inhibition liability.

Keywords: Cancer; HDM2; Protein-protein interaction; p53.

MeSH terms

  • Cytochrome P-450 CYP3A / metabolism*
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Structure
  • Phenylalanine / chemistry
  • Phenylalanine / pharmacology*
  • Protein Binding / drug effects
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship
  • Tumor Suppressor Protein p53 / antagonists & inhibitors*
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Small Molecule Libraries
  • Tumor Suppressor Protein p53
  • Phenylalanine
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2