4OHP

Human GKRP bound to AMG-3227 and S6P

4OHP の概要

• エントリーDOI: 10.2210/pdb4ohp/pdb
• 関連するPDBエントリー: 4OHK 4OHM 4OHO 4OLH 4OP1 4OP2 4OP3
• 分子名称: 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)
• 機能のキーワード: sis domains, regulatory protein - binds to and inhibits glucokinase, glucokinase, liver, carbohydrate binding protein-inhibitor complex, carbohydrate binding protein/inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: Q14397
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 145462.61

構造登録者

Jordan, S.R.,Chmait, S. (登録日: 2014-01-17, 公開日: 2014-07-30, 最終更新日: 2023-09-20)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.4 Å)