4ZJJ
PAK1 in complex with (S)-N-(tert-butyl)-3-((2-chloro-5-ethyl-8-fluoro-dibenzodiazepin-11-yl)amino)pyrrolidine-1-carboxamide
Summary for 4ZJJ
Entry DOI | 10.2210/pdb4zjj/pdb |
Related | 4ZJI |
Descriptor | Serine/threonine-protein kinase PAK 1, (S)-N-(tert-butyl)-3-((2-chloro-5-ethyl-8-fluoro-dibenzodiazepin-11-yl)amino)pyrrolidine-1-carboxamide, MAGNESIUM ION, ... (4 entities in total) |
Functional Keywords | pak1, inhibitor, kinase, allosteric, transferase |
Biological source | Homo sapiens (Human) |
Cellular location | Cytoplasm: Q13153 |
Total number of polymer chains | 4 |
Total formula weight | 135534.15 |
Authors | Gutmann, S.,Rummel, G. (deposition date: 2015-04-29, release date: 2015-06-24, Last modification date: 2024-05-08) |
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 Cited by 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: 26191365DOI: 10.1021/acsmedchemlett.5b00102 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (2.2 Å) |
Structure validation
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