4OHP

Human GKRP bound to AMG-3227 and S6P

Summary for 4OHP

• Entry DOI: 10.2210/pdb4ohp/pdb
• Related: 4OHK 4OHM 4OHO 4OLH 4OP1 4OP2 4OP3
• Descriptor: Glucokinase regulatory protein, 4-[(2S)-4-[(6-aminopyridin-3-yl)sulfonyl]-2-(prop-1-yn-1-yl)piperazin-1-yl]-N-methylbenzenesulfonamide, D-SORBITOL-6-PHOSPHATE, ... (7 entities in total)
• Functional Keywords: sis domains, regulatory protein - binds to and inhibits glucokinase, glucokinase, liver, carbohydrate binding protein-inhibitor complex, carbohydrate binding protein/inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: Q14397
• Total number of polymer chains: 2
• Total formula weight: 145462.61

Authors

Jordan, S.R.,Chmait, S. (deposition date: 2014-01-17, release date: 2014-07-30, Last modification date: 2023-09-20)

Primary citation

Nishimura, N.,Norman, M.H.,Liu, L.,Yang, K.C.,Ashton, K.S.,Bartberger, M.D.,Chmait, S.,Chen, J.,Cupples, R.,Fotsch, C.,Helmering, J.,Jordan, S.R.,Kunz, R.K.,Pennington, L.D.,Poon, S.F.,Siegmund, A.,Sivits, G.,Lloyd, D.J.,Hale, C.,St Jean, D.J.
Small molecule disruptors of the glucokinase-glucokinase regulatory protein interaction: 3. Structure-activity relationships within the aryl carbinol region of the N-arylsulfonamido-N'-arylpiperazine series.
J.Med.Chem., 57:3094-3116, 2014

PubMed Abstract: We have recently reported a novel approach to increase cytosolic glucokinase (GK) levels through the binding of a small molecule to its endogenous inhibitor, glucokinase regulatory protein (GKRP). These initial investigations culminated in the identification of 2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (1, AMG-3969), a compound that effectively enhanced GK translocation and reduced blood glucose levels in diabetic animals. Herein we report the results of our expanded SAR investigations that focused on modifications to the aryl carbinol group of this series. Guided by the X-ray cocrystal structure of compound 1 bound to hGKRP, we identified several potent GK-GKRP disruptors bearing a diverse set of functionalities in the aryl carbinol region. Among them, sulfoximine and pyridinyl derivatives 24 and 29 possessed excellent potency as well as favorable PK properties. When dosed orally in db/db mice, both compounds significantly lowered fed blood glucose levels (up to 58%).

PubMed: 24611879
DOI: 10.1021/jm5000497

Experimental method

X-RAY DIFFRACTION (2.4 Å)