5I0B

Structure of PAK4

Summary for 5I0B

• Entry DOI: 10.2210/pdb5i0b/pdb
• Descriptor: Serine/threonine-protein kinase PAK 4, 6-bromo-2-[1-methyl-3-(propan-2-yl)-1H-pyrazol-4-yl]-1H-imidazo[4,5-b]pyridine (2 entities in total)
• Functional Keywords: kinase, transferase-transferase inihibitor complex, transferase/transferase inihibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : O96013
• Total number of polymer chains: 1
• Total formula weight: 33745.03

Authors

Park, S.Y. (deposition date: 2016-02-03, release date: 2016-12-14, Last modification date: 2024-10-23)

Primary citation

Park, J.K.,Kim, S.,Han, Y.J.,Kim, S.H.,Kang, N.S.,Lee, H.,Park, S.Y.
The discovery and the structural basis of an imidazo[4,5-b]pyridine-based p21-activated kinase 4 inhibitor
Bioorg. Med. Chem. Lett., 26:2580-2583, 2016

PubMed Abstract: p21-Activated kinases (PAKs) which belong to the family of ste20 serine/threonine protein kinases regulate cytoskeletal reorganization, cell motility, cell proliferation, and oncogenic transformation which are all related to the cellular functions during cancer induction and metastasis. The fact that PAK mutations are detected in multiple tumor tissues makes PAKs a novel therapeutic drug target. In this study, an imidazo[4,5-b]pyridine-based PAK4 inhibitor, KY-04045 (6-Bromo-2-(3-isopropyl-1-methyl-1H-pyrazol-4-yl)-1H-imidazo[4,5-b]pyridine), was discovered using a virtual site-directed fragment-based drug design and was validated using an inhibition assay. Although PAK4 affinity to KY-04045 seems much weaker than that of the reported PAK4 inhibitors, the location of KY-04045 is clearly defined in the structure of PAK4 co-crystallized with KY-04045. The crystal structure illustrates that the pyrazole and imidazopyridine rings of KY-04045 are sufficient for mediating PAK4 hinge loop interaction. Hence, we believe that KY-04045 can be exploited as a basic building block in designing novel imidazo[4,5-b]pyridine-based PAK4 inhibitors.

PubMed: 27117431
DOI: 10.1016/j.bmcl.2016.04.037

Experimental method

X-RAY DIFFRACTION (3.09 Å)