7NA4

HDM2 in complex with compound 63

7NA4 の概要

• エントリーDOI: 10.2210/pdb7na4/pdb
• 分子名称: 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)
• 機能のキーワード: p53, drug design, protein-protein interactions, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 13349.09

構造登録者

Scapin, G. (登録日: 2021-06-19, 公開日: 2021-11-10, 最終更新日: 2024-05-22)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.84 Å)