4op2 | pdb_00004op2
GKRP bound to AMG-0471 and Sorbitol-6-Phosphate
Structural highlights
FunctionGCKR_HUMAN Inhibits glucokinase by forming an inactive complex with this enzyme. Publication Abstract from PubMedThe glucokinase-glucokinase regulatory protein (GK-GKRP) complex plays an important role in controlling glucose homeostasis in the liver. We have recently disclosed a series of arylpiperazines as in vitro and in vivo disruptors of the GK-GKRP complex with efficacy in rodent models of type 2 diabetes mellitus (T2DM). Herein, we describe a new class of aryl sulfones as disruptors of the GK-GKRP complex, where the central piperazine scaffold has been replaced by an aromatic group. Conformational analysis and exploration of the structure-activity relationships of this new class of compounds led to the identification of potent GK-GKRP disruptors. Further optimization of this novel series delivered thiazole sulfone 93, which was able to disrupt the GK-GKRP interaction in vitro and in vivo and, by doing so, increases cytoplasmic levels of unbound GK. Small Molecule Disruptors of the Glucokinase-Glucokinase Regulatory Protein Interaction: 5. A Novel Aryl Sulfone Series, Optimization Through Conformational Analysis.,Tamayo NA, Norman MH, Bartberger MD, Hong FT, Bo Y, Liu L, Nishimura N, Yang KC, Tadesse S, Fotsch C, Chen J, Chmait S, Cupples R, Hale C, Jordan SR, Lloyd DJ, Sivits G, Van G, St Jean DJ Jr J Med Chem. 2015 Jun 11;58(11):4462-82. doi: 10.1021/jm5018175. Epub 2015 Jun 1. PMID:25914941[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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