3IMX

Crystal Structure of human glucokinase in complex with a synthetic activator

Summary for 3IMX

• Entry DOI: 10.2210/pdb3imx/pdb
• Descriptor: Glucokinase, alpha-D-glucopyranose, (2R)-3-cyclopentyl-N-(5-methoxy[1,3]thiazolo[5,4-b]pyridin-2-yl)-2-{4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}propanamide, ... (5 entities in total)
• Functional Keywords: sugar kinase, atp-binding, glycolysis, kinase, nucleotide-binding, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 51655.64

Authors

Stams, T.,Vash, B. (deposition date: 2009-08-11, release date: 2009-10-06, Last modification date: 2023-09-06)

Primary citation

Bebernitz, G.R.,Beaulieu, V.,Dale, B.A.,Deacon, R.,Duttaroy, A.,Gao, J.,Grondine, M.S.,Gupta, R.C.,Kakmak, M.,Kavana, M.,Kirman, L.C.,Liang, J.,Maniara, W.M.,Munshi, S.,Nadkarni, S.S.,Schuster, H.F.,Stams, T.,St Denny, I.,Taslimi, P.M.,Vash, B.,Caplan, S.L.
Investigation of functionally liver selective glucokinase activators for the treatment of type 2 diabetes.
J.Med.Chem., 52:6142-6152, 2009

PubMed Abstract: Type 2 diabetes is a polygenic disease which afflicts nearly 200 million people worldwide and is expected to increase to near epidemic levels over the next 10-15 years. Glucokinase (GK) activators are currently under investigation by a number of pharmaceutical companies with only a few reaching early clinical evaluation. A GK activator has the promise of potentially affecting both the beta-cells of the pancreas, by improving glucose sensitive insulin secretion, as well as the liver, by reducing uncontrolled glucose output and restoring post-prandial glucose uptake and storage as glycogen. Herein, we report our efforts on a sulfonamide chemotype with the aim to generate liver selective GK activators which culminated in the discovery of 3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide (17c). This compound activated the GK enzyme (alphaK(a) = 39 nM) in vitro at low nanomolar concentrations and significantly reduced glucose levels during an oral glucose tolerance test in normal mice.

PubMed: 19746978
DOI: 10.1021/jm900839k

Experimental method

X-RAY DIFFRACTION (2 Å)