3QD4

Phosphoinositide-Dependent Kinase-1 (PDK1) kinase domain with 1,1-Dimethylethyl{(3R,5R)-1-[2-amino-6-(3-amino-1H-indazol-6-yl)-4-pyrimidinyl]-5-methyl-3-piperidinyl}carbamate

3QD4 の概要

• エントリーDOI: 10.2210/pdb3qd4/pdb
• 関連するPDBエントリー: 3NUN 3NUS 3NUU 3NUY 3QCQ 3QCS 3QCX 3QCY 3QD0 3QD3
• 分子名称: 3-phosphoinositide-dependent protein kinase 1, tert-butyl {(3R,5R)-1-[2-amino-6-(3-amino-2H-indazol-6-yl)pyrimidin-4-yl]-5-methylpiperidin-3-yl}carbamate, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: kinase domain, agc kinase, signal tranduction, atp & phosphoinositide, phosphorylation on s241, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: O15530
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 36187.44

構造登録者

Medina, J.R.,Becker, C.J.,Blackledge, C.W.,Duquenne, C.,Feng, Y.,Grant, S.W.,Heerding, D.,Li, W.H.,Miller, W.H.,Romeril, S.P.,Scherzer, D.,Shu, A.,Bobko, M.A.,Chadderton, A.R.,Dumble, M.,Gradiner, C.M.,Gilbert, S.,Liu, Q.,Rabindran, S.K.,Sudakin, V.,Xiang, H.,Brady, P.G.,Campobasso, N.,Ward, P.,Axten, J.M. (登録日: 2011-01-17, 公開日: 2011-03-09, 最終更新日: 2024-02-21)

主引用文献

Medina, J.R.,Becker, C.J.,Blackledge, C.W.,Duquenne, C.,Feng, Y.,Grant, S.W.,Heerding, D.,Li, W.H.,Miller, W.H.,Romeril, S.P.,Scherzer, D.,Shu, A.,Bobko, M.A.,Chadderton, A.R.,Dumble, M.,Gardiner, C.M.,Gilbert, S.,Liu, Q.,Rabindran, S.K.,Sudakin, V.,Xiang, H.,Brady, P.G.,Campobasso, N.,Ward, P.,Axten, J.M.
Structure-Based Design of Potent and Selective 3-Phosphoinositide-Dependent Kinase-1 (PDK1) Inhibitors.
J.Med.Chem., 54:1871-1895, 2011

PubMed Abstract: Phosphoinositide-dependent protein kinase-1(PDK1) is a master regulator of the AGC family of kinases and an integral component of the PI3K/AKT/mTOR pathway. As this pathway is among the most commonly deregulated across all cancers, a selective inhibitor of PDK1 might have utility as an anticancer agent. Herein we describe our lead optimization of compound 1 toward highly potent and selective PDK1 inhibitors via a structure-based design strategy. The most potent and selective inhibitors demonstrated submicromolar activity as measured by inhibition of phosphorylation of PDK1 substrates as well as antiproliferative activity against a subset of AML cell lines. In addition, reduction of phosphorylation of PDK1 substrates was demonstrated in vivo in mice bearing OCl-AML2 xenografts. These observations demonstrate the utility of these molecules as tools to further delineate the biology of PDK1 and the potential pharmacological uses of a PDK1 inhibitor.

PubMed: 21341675
DOI: 10.1021/jm101527u

実験手法

X-RAY DIFFRACTION (2.3 Å)