7NA4

HDM2 in complex with compound 63

Summary for 7NA4

• Entry DOI: 10.2210/pdb7na4/pdb
• Descriptor: Isoform 11 of E3 ubiquitin-protein ligase Mdm2, 3-[4-(5-chloropyridin-3-yl)-2-[(R)-cyclopropyl(ethoxy)methyl]-3-{(1R)-1-[(1r,4R)-4-methylcyclohexyl]ethyl}-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one, GLYCEROL, ... (5 entities in total)
• Functional Keywords: p53, drug design, protein-protein interactions, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 13349.09

Authors

Scapin, G. (deposition date: 2021-06-19, release date: 2021-11-10, Last modification date: 2024-05-22)

Primary citation

Reutershan, M.H.,Machacek, M.R.,Altman, M.D.,Bogen, S.,Cai, M.,Cammarano, C.,Chen, D.,Christopher, M.,Cryan, J.,Daublain, P.,Fradera, X.,Geda, P.,Goldenblatt, P.,Hill, A.D.,Kemper, R.A.,Kutilek, V.,Li, C.,Martinez, M.,McCoy, M.,Nair, L.,Pan, W.,Thompson, C.F.,Scapin, G.,Shizuka, M.,Spatz, M.L.,Steinhuebel, D.,Sun, B.,Voss, M.E.,Wang, X.,Yang, L.,Yeh, T.C.,Dussault, I.,Marshall, C.G.,Trotter, B.W.
Discovery of MK-4688 : an Efficient Inhibitor of the HDM2-p53 Protein-Protein Interaction.
J.Med.Chem., 64:16213-16241, 2021

PubMed 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 (compound ), a highly potent, selective, and low-molecular-weight inhibitor suitable for clinical investigation.

PubMed: 34714078
DOI: 10.1021/acs.jmedchem.1c01524

Experimental method

X-RAY DIFFRACTION (1.84 Å)