5HMI

HDM2 in complex with a 3,3-Disubstituted Piperidine

Summary for 5HMI

• Entry DOI: 10.2210/pdb5hmi/pdb
• Related: 5HMH 5HMK
• Descriptor: E3 ubiquitin-protein ligase Mdm2, {4-[2-(2-hydroxyethoxy)phenyl]piperazin-1-yl}[(2R,3S)-2-propyl-1-{[4-(trifluoromethyl)pyridin-3-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]methanone, SULFATE ION, ... (4 entities in total)
• Functional Keywords: oncology, e3 ubiquitin-protein ligase, p53/tp53, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus, nucleoplasm: Q00987
• Total number of polymer chains: 2
• Total formula weight: 25531.33

Authors

Scapin, G. (deposition date: 2016-01-16, release date: 2016-04-06, Last modification date: 2024-03-06)

Primary citation

Bogen, S.L.,Pan, W.,Gibeau, C.R.,Lahue, B.R.,Ma, Y.,Nair, L.G.,Seigel, E.,Shipps, G.W.,Tian, Y.,Wang, Y.,Lin, Y.,Liu, M.,Liu, S.,Mirza, A.,Wang, X.,Lipari, P.,Seidel-Dugan, C.,Hicklin, D.J.,Bishop, W.R.,Rindgen, D.,Nomeir, A.,Prosise, W.,Reichert, P.,Scapin, G.,Strickland, C.,Doll, R.J.
Discovery of Novel 3,3-Disubstituted Piperidines as Orally Bioavailable, Potent, and Efficacious HDM2-p53 Inhibitors.
Acs Med.Chem.Lett., 7:324-329, 2016

PubMed Abstract: A new subseries of substituted piperidines as p53-HDM2 inhibitors exemplified by 21 has been developed from the initial lead 1. Research focused on optimization of a crucial HDM2 Trp23-ligand interaction led to the identification of 2-(trifluoromethyl)thiophene as the preferred moiety. Further investigation of the Leu26 pocket resulted in potent, novel substituted piperidine inhibitors of the HDM2-p53 interaction that demonstrated tumor regression in several human cancer xenograft models in mice. The structure of HDM2 in complex with inhibitors 3, 10, and 21 is described.

PubMed: 26985323
DOI: 10.1021/acsmedchemlett.5b00472

Experimental method

X-RAY DIFFRACTION (1.74 Å)