4NJD

Structure of p21-activated kinase 4 with a novel inhibitor KY-04031

Summary for 4NJD

• Entry DOI: 10.2210/pdb4njd/pdb
• Descriptor: Serine/threonine-protein kinase PAK 4, N-(1H-indazol-5-yl)-N'-[2-(1H-indol-3-yl)ethyl]-6-methoxy-1,3,5-triazine-2,4-diamine (3 entities in total)
• Functional Keywords: kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: O96013
• Total number of polymer chains: 1
• Total formula weight: 33825.28

Authors

Park, S. (deposition date: 2013-11-09, release date: 2014-05-21, Last modification date: 2024-10-16)

Primary citation

Ryu, B.J.,Kim, S.,Min, B.,Kim, K.Y.,Lee, J.S.,Park, W.J.,Lee, H.,Kim, S.H.,Park, S.
Discovery and the structural basis of a novel p21-activated kinase 4 inhibitor.
Cancer Lett., 349:45-50, 2014

PubMed Abstract: Functional versatility and elevated expression in cancers have endowed p21-activated kinase 4 (PAK4) as one of the first-in-class anti-cancer drug target. In this study, a novel PAK4 inhibitor, KY-04031 (N(2)-(2-(1H-indol-3-yl)ethyl)-N(4)-(1H-indazol-5-yl)-6-methoxy-1,3,5-triazine-2,4-diamine), was discovered using a high-throughput screening. Analysis of the complex crystal structure illustrated that both indole and indazole of KY-04031 are responsible for PAK4 hinge interaction. Moreover, the molecule's triazine core was found to mimic the ribose of the natural ATP substrate. The cell-based anti-cancer potency of KY-04031 was less effective than the pyrroloaminopyrazoles; however, the unique molecular feature of KY-04031 can be exploited in designing new PAK4 inhibitors.

PubMed: 24704155
DOI: 10.1016/j.canlet.2014.03.024

Experimental method

X-RAY DIFFRACTION (2.5 Å)