4O0T

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

Summary for 4O0T

• Entry DOI: 10.2210/pdb4o0t/pdb
• Related: 4O0R 4O0V 4O0X 4O0Y
• Descriptor: Serine/threonine-protein kinase PAK 1, 1-({1-(2-aminopyrimidin-4-yl)-2-[(2-methoxyethyl)amino]-1H-benzimidazol-6-yl}ethynyl)cyclohexanol (3 entities in total)
• Functional Keywords: pak1, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: Q13153
• Total number of polymer chains: 2
• Total formula weight: 67495.49

Authors

Oh, A.,Tam, C.,Wang, W. (deposition date: 2013-12-14, release date: 2014-02-12, Last modification date: 2024-02-28)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.6 Å)