5L58

Crystal structure of Iso-citrate Dehydrogenase 1 [IDH1 (R132H)] in complex with a novel inhibitor (Compound 2)

Summary for 5L58

• Entry DOI: 10.2210/pdb5l58/pdb
• Descriptor: Isocitrate dehydrogenase [NADP] cytoplasmic, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 2-[(3~{R})-1-[6-cyclohexylsulfanyl-5-[[(1~{R},3~{S})-5-oxidanyl-2-adamantyl]carbamoyl]pyridin-2-yl]pyrrolidin-3-yl]ethanoic acid (3 entities in total)
• Functional Keywords: iso-citrate dehydrogenase, allosteric, oxidoreductase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 47670.97

Authors

Levy, C. (deposition date: 2016-05-28, release date: 2016-12-14, Last modification date: 2024-11-20)

Primary citation

Jones, S.,Ahmet, J.,Ayton, K.,Ball, M.,Cockerill, M.,Fairweather, E.,Hamilton, N.,Harper, P.,Hitchin, J.,Jordan, A.,Levy, C.,Lopez, R.,McKenzie, E.,Packer, M.,Plant, D.,Simpson, I.,Simpson, P.,Sinclair, I.,Somervaille, T.C.,Small, H.,Spencer, G.J.,Thomson, G.,Tonge, M.,Waddell, I.,Walsh, J.,Waszkowycz, B.,Wigglesworth, M.,Wiseman, D.H.,Ogilvie, D.
Discovery and Optimization of Allosteric Inhibitors of Mutant Isocitrate Dehydrogenase 1 (R132H IDH1) Displaying Activity in Human Acute Myeloid Leukemia Cells.
J.Med.Chem., 59:11120-11137, 2016

PubMed Abstract: A collaborative high throughput screen of 1.35 million compounds against mutant (R132H) isocitrate dehydrogenase IDH1 led to the identification of a novel series of inhibitors. Elucidation of the bound ligand crystal structure showed that the inhibitors exhibited a novel binding mode in a previously identified allosteric site of IDH1 (R132H). This information guided the optimization of the series yielding submicromolar enzyme inhibitors with promising cellular activity. Encouragingly, one compound from this series was found to induce myeloid differentiation in primary human IDH1 R132H AML cells in vitro.

PubMed: 28002956
DOI: 10.1021/acs.jmedchem.6b01320

Experimental method

X-RAY DIFFRACTION (3.04 Å)