5OAI

Structure of MDM2 with low molecular weight inhibitor

Summary for 5OAI

• Entry DOI: 10.2210/pdb5oai/pdb
• Descriptor: E3 ubiquitin-protein ligase Mdm2, 3-[(1~{R})-2-(~{tert}-butylamino)-1-[methanoyl-[[3,4,5-tris(fluoranyl)phenyl]methyl]amino]-2-oxidanylidene-ethyl]-6-chloranyl-1~{H}-indole-2-carboxylic acid (3 entities in total)
• Functional Keywords: p53, mdm2, mdmx, protein-protein interaction, cancer, inhibitor, ligase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 11895.25

Authors

Twarda-Clapa, A.,Neochoritis, C.G.,Grudnik, P.,Dubin, G.,Domling, A.,Holak, T.A. (deposition date: 2017-06-22, release date: 2019-02-13, Last modification date: 2024-01-17)

Primary citation

Skalniak, L.,Twarda-Clapa, A.,Neochoritis, C.G.,Surmiak, E.,Machula, M.,Wisniewska, A.,Labuzek, B.,Ali, A.M.,Krzanik, S.,Dubin, G.,Groves, M.,Domling, A.,Holak, T.A.
A fluorinated indole-based MDM2 antagonist selectively inhibits the growth of p53wtosteosarcoma cells.
Febs J., 286:1360-1374, 2019

PubMed Abstract: The p53 protein is engaged in the repair of DNA mutations and elimination of heavily damaged cells, providing anticancer protection. Dysregulation of p53 activity is a crucial step in carcinogenesis. This dysregulation is often caused by the overexpression of negative regulators of p53, among which MDM2 is the most prominent one. Antagonizing MDM2 with small molecules restores the activity of p53 in p53 wild-type (p53 ) cells and thus provides positive outcomes in the treatment of p53 cancers. Previously, we have reported the discovery of a panel of fluoro-substituted indole-based antagonists of MDM2. Here, we demonstrate the biological activity and stereoselectivity of the most active compound from this series. Both enantiomers of the esterified form of the compound, as well as its corresponding carboxylic acids, were found active in fluorescence polarization (FP) assay, nuclear magnetic resonance (NMR) and microscale thermophoresis (MST) assay, with K and K values around 1 μm. From these four compounds, the esterified enantiomer (R)-5a was active in cells, which was evidenced by the increase of p53 levels, the induced expression of p53-target genes (CDKN1A and MDM2), the selective induction of cell cycle arrest, and selective growth inhibition of p53 U-2 OS and SJSA-1 compared to p53 SAOS-2 cells. The analysis of the crystal structure of human MDM2 in complex with the compound (R)-6a (carboxylic acid of the active (R)-5a compound) revealed the classical three-finger binding mode. Altogether, our data demonstrate the activity of the compound and provide the structural basis for further structure optimization.

PubMed: 30715803
DOI: 10.1111/febs.14774

Experimental method

X-RAY DIFFRACTION (2 Å)