4ZY4

Crystal structure of P21 activated kinase 1 in complex with an inhibitor compound 4

Summary for 4ZY4

• Entry DOI: 10.2210/pdb4zy4/pdb
• Related: 4ZY5 4ZY6
• Descriptor: Serine/threonine-protein kinase PAK 1, 2-(4-aminopiperidin-1-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine, SULFATE ION, ... (5 entities in total)
• Functional Keywords: kinase, inhibitor, complex, 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: 68032.21

Authors

Rouge, R.,Wang, W. (deposition date: 2015-05-21, release date: 2015-07-01, Last modification date: 2015-07-15)

Primary citation

Crawford, J.J.,Lee, W.,Aliagas, I.,Mathieu, S.,Hoeflich, K.P.,Zhou, W.,Wang, W.,Rouge, L.,Murray, L.,La, H.,Liu, N.,Fan, P.W.,Cheong, J.,Heise, C.E.,Ramaswamy, S.,Mintzer, R.,Liu, Y.,Chao, Q.,Rudolph, J.
Structure-Guided Design of Group I Selective p21-Activated Kinase Inhibitors.
J.Med.Chem., 58:5121-5136, 2015

PubMed Abstract: The p21-activated kinases (PAKs) play important roles in cytoskeletal organization, cellular morphogenesis, and survival and have generated significant attention as potential therapeutic targets for cancer. Following a high-throughput screen, we identified an aminopyrazole scaffold-based series that was optimized to yield group I selective PAK inhibitors. A structure-based design effort aimed at targeting the ribose pocket for both potency and selectivity led to much-improved group I vs II selectivity. Early lead compounds contained a basic primary amine, which was found to be a major metabolic soft spot with in vivo clearance proceeding predominantly via N-acetylation. We succeeded in identifying replacements with improved metabolic stability, leading to compounds with lower in vivo rodent clearance and excellent group I PAK selectivity.

PubMed: 26030457
DOI: 10.1021/acs.jmedchem.5b00572

Experimental method

X-RAY DIFFRACTION (2.6 Å)