4O0X

Back pocket flexibility provides group-II PAK selectivity for type 1 kinase inhibitors

4O0X の概要

• エントリーDOI: 10.2210/pdb4o0x/pdb
• 関連するPDBエントリー: 4O0R 4O0T 4O0V 4O0Y
• 分子名称: Serine/threonine-protein kinase PAK 4, 1-{[1-(4-amino-1,3,5-triazin-2-yl)-2-methyl-1H-benzimidazol-6-yl]ethynyl}cyclohexanol (3 entities in total)
• 機能のキーワード: pak4, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm : O96013
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 33416.82

構造登録者

Rouge, L.,Tam, C.,Wang, W. (登録日: 2013-12-14, 公開日: 2014-02-12, 最終更新日: 2024-10-09)

主引用文献

Staben, S.T.,Feng, J.A.,Lyle, K.,Belvin, M.,Boggs, J.,Burch, J.D.,Chua, C.C.,Cui, H.,Dipasquale, A.G.,Friedman, L.S.,Heise, C.,Koeppen, H.,Kotey, A.,Mintzer, R.,Oh, A.,Roberts, D.A.,Rouge, L.,Rudolph, J.,Tam, C.,Wang, W.,Xiao, Y.,Young, A.,Zhang, Y.,Hoeflich, K.P.
Back Pocket Flexibility Provides Group II p21-Activated Kinase (PAK) Selectivity for Type I 1/2 Kinase Inhibitors.
J.Med.Chem., 57:1033-1045, 2014

PubMed Abstract: Structure-based methods were used to design a potent and highly selective group II p21-activated kinase (PAK) inhibitor with a novel binding mode, compound 17. Hydrophobic interactions within a lipophilic pocket past the methionine gatekeeper of group II PAKs approached by these type I 1/2 binders were found to be important for improving potency. A structure-based hypothesis and strategy for achieving selectivity over group I PAKs, and the broad kinome, based on unique flexibility of this lipophilic pocket, is presented. A concentration-dependent decrease in tumor cell migration and invasion in two triple-negative breast cancer cell lines was observed with compound 17.

PubMed: 24432870
DOI: 10.1021/jm401768t

実験手法

X-RAY DIFFRACTION (2.483 Å)