2. Academic Validation
  3. Phe19 modification of HDM2-p53 PPI inhibitors to alleviate CYP3A4 metabolism/mechanism-based inhibition liability

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.
Yuan Tian 1,  Brian R Lahue 1,  Yao Ma 1,  Latha G Nair 2,  Weidong Pan 2,  Ronald J Doll 2,  Timothy Guzi 1,  Yao Ma 1,  Yaolin Wang 2,  Stéphane L Bogen 3
Affiliations

Affiliations

  • 1 Merck & Co Inc, 33 Avenue Louis Pasteur, Boston, MA 02115, United States.
  • 2 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
  • 3 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States. Electronic address: [email protected].
PMID: 35158044 DOI: 10.1016/j.bmcl.2022.128625
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.

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