4ZLO

Serine/threonine-protein kinase PAK1 complexed with a dibenzodiazepine: identification of an allosteric site on PAK1

Summary for 4ZLO

• Entry DOI: 10.2210/pdb4zlo/pdb
• Related: 4ZJI 4ZJJ
• Descriptor: Serine/threonine-protein kinase PAK 1, 2,8-difluoro-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine, GLYCEROL, ... (4 entities in total)
• Functional Keywords: dibenzodazepine, pak1, kinase, allosteric inhibitor, 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: 67098.91

Authors

Bellamacina, C.R.,Bussiere, D.E. (deposition date: 2015-05-01, release date: 2015-08-05, Last modification date: 2024-10-23)

Primary citation

Karpov, A.S.,Amiri, P.,Bellamacina, C.,Bellance, M.H.,Breitenstein, W.,Daniel, D.,Denay, R.,Fabbro, D.,Fernandez, C.,Galuba, I.,Guerro-Lagasse, S.,Gutmann, S.,Hinh, L.,Jahnke, W.,Klopp, J.,Lai, A.,Lindvall, M.K.,Ma, S.,Mobitz, H.,Pecchi, S.,Rummel, G.,Shoemaker, K.,Trappe, J.,Voliva, C.,Cowan-Jacob, S.W.,Marzinzik, A.L.
Optimization of a Dibenzodiazepine Hit to a Potent and Selective Allosteric PAK1 Inhibitor.
Acs Med.Chem.Lett., 6:776-781, 2015

PubMed Abstract: The discovery of inhibitors targeting novel allosteric kinase sites is very challenging. Such compounds, however, once identified could offer exquisite levels of selectivity across the kinome. Herein we report our structure-based optimization strategy of a dibenzodiazepine hit 1, discovered in a fragment-based screen, yielding highly potent and selective inhibitors of PAK1 such as 2 and 3. Compound 2 was cocrystallized with PAK1 to confirm binding to an allosteric site and to reveal novel key interactions. Compound 3 modulated PAK1 at the cellular level and due to its selectivity enabled valuable research to interrogate biological functions of the PAK1 kinase.

PubMed: 26191365
DOI: 10.1021/acsmedchemlett.5b00102

Experimental method

X-RAY DIFFRACTION (2.5 Å)