4OAS

co-crystal structure of MDM2 (17-111) in complex with compound 25

Summary for 4OAS

• Entry DOI: 10.2210/pdb4oas/pdb
• Related: 4ERE 4ERF
• Descriptor: E3 ubiquitin-protein ligase Mdm2, [(3R,5R,6S)-1-[(2S)-1-(tert-butylsulfonyl)butan-2-yl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid, SULFATE ION, ... (4 entities in total)
• Functional Keywords: mdm2. 53, protein-protein interaction, inhibitor, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus, nucleoplasm: Q00987
• Total number of polymer chains: 3
• Total formula weight: 35269.88

Authors

Huang, X. (deposition date: 2014-01-06, release date: 2014-02-19, Last modification date: 2024-02-28)

Primary citation

Sun, D.,Li, Z.,Rew, Y.,Gribble, M.,Bartberger, M.D.,Beck, H.P.,Canon, J.,Chen, A.,Chen, X.,Chow, D.,Deignan, J.,Duquette, J.,Eksterowicz, J.,Fisher, B.,Fox, B.M.,Fu, J.,Gonzalez, A.Z.,Gonzalez-Lopez De Turiso, F.,Houze, J.B.,Huang, X.,Jiang, M.,Jin, L.,Kayser, F.,Liu, J.J.,Lo, M.C.,Long, A.M.,Lucas, B.,McGee, L.R.,McIntosh, J.,Mihalic, J.,Oliner, J.D.,Osgood, T.,Peterson, M.L.,Roveto, P.,Saiki, A.Y.,Shaffer, P.,Toteva, M.,Wang, Y.,Wang, Y.C.,Wortman, S.,Yakowec, P.,Yan, X.,Ye, Q.,Yu, D.,Yu, M.,Zhao, X.,Zhou, J.,Zhu, J.,Olson, S.H.,Medina, J.C.
Discovery of AMG 232, a Potent, Selective, and Orally Bioavailable MDM2-p53 Inhibitor in Clinical Development.
J.Med.Chem., 57:1454-1472, 2014

PubMed Abstract: We recently reported the discovery of AM-8553 (1), a potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Continued research investigation of the N-alkyl substituent of this series, focused in particular on a previously underutilized interaction in a shallow cleft on the MDM2 surface, led to the discovery of a one-carbon tethered sulfone which gave rise to substantial improvements in biochemical and cellular potency. Further investigation produced AMG 232 (2), which is currently being evaluated in human clinical trials for the treatment of cancer. Compound 2 is an extremely potent MDM2 inhibitor (SPR KD = 0.045 nM, SJSA-1 EdU IC50 = 9.1 nM), with remarkable pharmacokinetic properties and in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft model (ED50 = 9.1 mg/kg).

PubMed: 24456472
DOI: 10.1021/jm401753e

Experimental method

X-RAY DIFFRACTION (1.7 Å)