Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization

• Published in: Proceedings of the National Academy of Sciences - PNAS 2012-07, Vol.109 (29), p.11788-11793
• Main Authors: Graves, Bradford, Thompson, Thelma, Xia, Mingxuan, Janson, Cheryl, Lukacs, Christine, Deo, Dayanand, Di Lello, Paola, Fry, David, Garvie, Colin, Huang, Kuo-Sen, Gao, Lin, Tovar, Christian, Lovey, Allen, Wanner, Jutta, Vassilev, Lyubomir T
• Format: Article
• Language: English
• Subjects: antagonists; Apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Biological Sciences; Blotting, Western; Cancer therapies; Cell cycle; cell cycle checkpoints; Cell Line, Tumor; Crystallization; Dimerization; Fluorescence Resonance Energy Transfer; Humans; Hydantoins - pharmacology; mechanism of action; mice; Models, Molecular; Molecules; neoplasm cells; neoplasms; Nuclear Magnetic Resonance, Biomolecular; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - chemistry; Proteins; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - chemistry; Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors; Proto-Oncogene Proteins c-mdm2 - chemistry; Signal Transduction - drug effects; Signal Transduction - physiology; Tetrazolium Salts; therapeutics; Thiazoles; Tumor Suppressor Protein p53 - metabolism; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1203789109

Activation of p53 tumor suppressor by antagonizing its negative regulator murine double minute (MDM)2 has been considered an attractive strategy for cancer therapy and several classes of p53-MDM2 binding inhibitors have been developed. However, these compounds do not inhibit the p53-MDMX interaction, and their effectiveness can be compromised in tumors overexpressing MDMX. Here, we identify small molecules that potently block p53 binding with both MDM2 and MDMX by inhibitor-driven homo- and/or heterodimerization of MDM2 and MDMX proteins. Structural studies revealed that the inhibitors bind into and occlude the p53 pockets of MDM2 and MDMX by inducing the formation of dimeric protein complexes kept together by a dimeric small-molecule core. This mode of action effectively stabilized p53 and activated p53 signaling in cancer cells, leading to cell cycle arrest and apoptosis. Dual MDM2/MDMX antagonists restored p53 apoptotic activity in the presence of high levels of MDMX and may offer a more effective therapeutic modality for MDMX-overexpressing cancers.