3JZK

crystal structure of MDM2 with chromenotriazolopyrimidine 1

Summary for 3JZK

• Entry DOI: 10.2210/pdb3jzk/pdb
• Descriptor: E3 ubiquitin-protein ligase Mdm2, (6R,7S)-6,7-bis(4-bromophenyl)-7,11-dihydro-6H-chromeno[4,3-d][1,2,4]triazolo[1,5-a]pyrimidine (3 entities in total)
• Functional Keywords: mdm2, p53, inhibitor, alternative splicing, cytoplasm, host-virus interaction, ligase, metal-binding, nucleus, phosphoprotein, proto-oncogene, ubl conjugation, ubl conjugation pathway, zinc, zinc-finger
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus, nucleoplasm: Q00987
• Total number of polymer chains: 1
• Total formula weight: 11692.27

Authors

Huang, X. (deposition date: 2009-09-23, release date: 2009-11-17, Last modification date: 2023-09-06)

Primary citation

Allen, J.G.,Bourbeau, M.P.,Wohlhieter, G.E.,Bartberger, M.D.,Michelsen, K.,Hungate, R.,Gadwood, R.C.,Gaston, R.D.,Evans, B.,Mann, L.W.,Matison, M.E.,Schneider, S.,Huang, X.,Yu, D.,Andrews, P.S.,Reichelt, A.,Long, A.M.,Yakowec, P.,Yang, E.Y.,Lee, T.A.,Oliner, J.D.
Discovery and optimization of chromenotriazolopyrimidines as potent inhibitors of the mouse double minute 2-tumor protein 53 protein-protein interaction.
J.Med.Chem., 52:7044-7053, 2009

PubMed Abstract: Tumor protein 53 (p53) is a critical regulator of cell cycle and apoptosis that is frequently disabled in human tumors. In many tumor types, p53 is deleted or mutated, but in others p53 is inactivated by overexpression or amplification of its negative regulator mouse double minute 2 (MDM2). A high-throughput screening effort identified 6,7-bis(4-bromophenyl)-7,12-dihydro-6H-chromeno[4,3-d][1,2,4]triazolo[1,5-a]pyrimidine as a potent inhibitor of the MDM2-p53 protein-protein interaction. This screening hit was found to be chemically unstable and difficult to handle due to poor DMSO solubility. Co-crystallization with the target protein helped to direct further optimization and provided a tractable lead series of novel MDM2-p53 inhibitors. In cellular assays, these compounds were shown to upregulate p53 protein levels and p53 signaling and to cause p53-dependent inhibition of proliferation and apoptosis.

PubMed: 19856920
DOI: 10.1021/jm900681h

Experimental method

X-RAY DIFFRACTION (2.1 Å)