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4OGN

Co-Crystal Structure of MDM2 with Inhbitor Compound 3

Summary for 4OGN
Entry DOI10.2210/pdb4ogn/pdb
DescriptorE3 ubiquitin-protein ligase Mdm2, 6-{[(3R,5R,6S)-1-[(1S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]methyl}pyridine-3-carboxylic acid, SULFATE ION, ... (4 entities in total)
Functional Keywordsp53, protein-protein interaction, ligase-ligase inhibitor complex, ligase/ligase inhibitor
Biological sourceHomo sapiens (human)
Cellular locationNucleus, nucleoplasm: Q00987
Total number of polymer chains1
Total formula weight12894.85
Authors
Shaffer, P.L.,Huang, X.,Yakowec, P.,Long, A.M. (deposition date: 2014-01-16, release date: 2014-04-02, Last modification date: 2023-09-20)
Primary citationGonzalez, A.Z.,Li, Z.,Beck, H.P.,Canon, J.,Chen, A.,Chow, D.,Duquette, J.,Eksterowicz, J.,Fox, B.M.,Fu, J.,Huang, X.,Houze, J.,Jin, L.,Li, Y.,Ling, Y.,Lo, M.C.,Long, A.M.,McGee, L.R.,McIntosh, J.,Oliner, J.D.,Osgood, T.,Rew, Y.,Saiki, A.Y.,Shaffer, P.,Wortman, S.,Yakowec, P.,Yan, X.,Ye, Q.,Yu, D.,Zhao, X.,Zhou, J.,Olson, S.H.,Sun, D.,Medina, J.C.
Novel Inhibitors of the MDM2-p53 Interaction Featuring Hydrogen Bond Acceptors as Carboxylic Acid Isosteres.
J.Med.Chem., 57:2963-2988, 2014
Cited by
PubMed Abstract: We previously reported the discovery of potent and selective morpholinone and piperidinone inhibitors of the MDM2-p53 interaction. These inhibitors have in common a carboxylic acid moiety that engages in an electrostatic interaction with MDM2-His96. Our continued search for potent and diverse inhibitors led to the discovery of novel replacements for these acids uncovering new interactions with the MDM2 protein. In particular, using pyridine or thiazole as isosteres of the carboxylic acid moiety resulted in very potent analogues. From these, AM-6761 (4) emerged as a potent inhibitor with remarkable biochemical (HTRF IC50 = 0.1 nM) and cellular potency (SJSA-1 EdU IC50 = 16 nM), as well as favorable pharmacokinetic properties. Compound 4 also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 11 mg/kg. Optimization efforts toward the discovery of these inhibitors as well as the new interactions observed with the MDM2 protein are described herein.
PubMed: 24601644
DOI: 10.1021/jm401911v
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.377 Å)
Structure validation

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