2. Academic Validation
  3. Discovery of MK-4688: an Efficient Inhibitor of the HDM2-p53 Protein-Protein Interaction

Discovery of MK-4688: an Efficient Inhibitor of the HDM2-p53 Protein-Protein Interaction

  • J Med Chem. 2021 Nov 11;64(21):16213-16241. doi: 10.1021/acs.jmedchem.1c01524.
Michael H Reutershan 1,  Michelle R Machacek 1,  Michael D Altman 1,  Stephane Bogen 2,  Mingmei Cai 1,  Carolyn Cammarano 1,  Dapeng Chen 1,  Matthew Christopher 1,  John Cryan 1,  Pierre Daublain 1,  Xavier Fradera 1,  Prasanthi Geda 1,  Peter Goldenblatt 1,  Armetta D Hill 1,  Raymond A Kemper 1,  Victoria Kutilek 1,  Chaomin Li 1,  Michelle Martinez 1,  Mark McCoy 2,  Latha Nair 2,  Weidong Pan 2,  Christopher F Thompson 1,  Giovanna Scapin 2,  Manami Shizuka 1,  Marianne L Spatz 1,  Dietrich Steinhuebel 1,  Binyuan Sun 1,  Matthew E Voss 3,  Xiao Wang 4,  Liping Yang 1,  Tammie C Yeh 1,  Isabelle Dussault 1,  C Gary Marshall 1,  B Wesley Trotter 1
Affiliations

Affiliations

  • 1 Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
  • 2 Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, New Jersey 07032, United States.
  • 3 Albany Molecular Research Inc., 61 Science Park Road, Singapore (West) 117525, Singapore.
  • 4 Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
PMID: 34714078 DOI: 10.1021/acs.jmedchem.1c01524
Abstract

Identification of low-dose, low-molecular-weight, drug-like inhibitors of protein-protein interactions (PPIs) is a challenging area of research. Despite the challenges, the therapeutic potential of PPI inhibition has driven significant efforts toward this goal. Adding to recent success in this area, we describe herein our efforts to optimize a novel purine carboxylic acid-derived inhibitor of the HDM2-p53 PPI into a series of low-projected dose inhibitors with overall favorable pharmacokinetic and physical properties. Ultimately, a strategy focused on leveraging known binding hot spots coupled with biostructural information to guide the design of conformationally constrained analogs and a focus on efficiency metrics led to the discovery of MK-4688 (compound 56), a highly potent, selective, and low-molecular-weight inhibitor suitable for clinical investigation.

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