3NAX

PDK1 in complex with inhibitor MP7

3NAX の概要

• エントリーDOI: 10.2210/pdb3nax/pdb
• 関連するPDBエントリー: 3NAY
• 分子名称: 3-phosphoinositide-dependent protein kinase 1, 1-(3,4-difluorobenzyl)-2-oxo-N-{(1R)-2-[(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)oxy]-1-phenylethyl}-1,2-dihydropyridine-3-carboxamide (3 entities in total)
• 機能のキーワード: kinase, serine/threonine protein kinase, transferase
• 由来する生物種: Homo sapiens
• 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: 36610.96

構造登録者

Yan, Y.,Munshi, S.K.,Allison, T. (登録日: 2010-06-02, 公開日: 2010-11-24, 最終更新日: 2024-02-21)

主引用文献

Nagashima, K.,Shumway, S.D.,Sathyanarayanan, S.,Chen, A.H.,Dolinski, B.,Xu, Y.,Keilhack, H.,Nguyen, T.,Wiznerowicz, M.,Li, L.,Lutterbach, B.A.,Chi, A.,Paweletz, C.,Allison, T.,Yan, Y.,Munshi, S.K.,Klippel, A.,Kraus, M.,Bobkova, E.V.,Deshmukh, S.,Xu, Z.,Mueller, U.,Szewczak, A.A.,Pan, B.S.,Richon, V.,Pollock, R.,Blume-Jensen, P.,Northrup, A.,Andersen, J.N.
Genetic and pharmacological inhibition of PDK1 in cancer cells: characterization of a selective allosteric kinase inhibitor.
J.Biol.Chem., 286:6433-6448, 2011

PubMed Abstract: Phosphoinositide-dependent kinase 1 (PDK1) is a critical activator of multiple prosurvival and oncogenic protein kinases and has garnered considerable interest as an oncology drug target. Despite progress characterizing PDK1 as a therapeutic target, pharmacological support is lacking due to the prevalence of nonspecific inhibitors. Here, we benchmark literature and newly developed inhibitors and conduct parallel genetic and pharmacological queries into PDK1 function in cancer cells. Through kinase selectivity profiling and x-ray crystallographic studies, we identify an exquisitely selective PDK1 inhibitor (compound 7) that uniquely binds to the inactive kinase conformation (DFG-out). In contrast to compounds 1-5, which are classical ATP-competitive kinase inhibitors (DFG-in), compound 7 specifically inhibits cellular PDK1 T-loop phosphorylation (Ser-241), supporting its unique binding mode. Interfering with PDK1 activity has minimal antiproliferative effect on cells growing as plastic-attached monolayer cultures (i.e. standard tissue culture conditions) despite reduced phosphorylation of AKT, RSK, and S6RP. However, selective PDK1 inhibition impairs anchorage-independent growth, invasion, and cancer cell migration. Compound 7 inhibits colony formation in a subset of cancer cell lines (four of 10) and primary xenograft tumor lines (nine of 57). RNAi-mediated knockdown corroborates the PDK1 dependence in cell lines and identifies candidate biomarkers of drug response. In summary, our profiling studies define a uniquely selective and cell-potent PDK1 inhibitor, and the convergence of genetic and pharmacological phenotypes supports a role of PDK1 in tumorigenesis in the context of three-dimensional in vitro culture systems.

PubMed: 21118801
DOI: 10.1074/jbc.M110.156463

実験手法

X-RAY DIFFRACTION (1.75 Å)