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Discovery and the structural basis of a novel p21-activated kinase 4 inhibitor
- Authors
- Ryu, Byung Jun; Kim, Sunmin; Min, Bora; Kim, Keon Young; Lee, Jin Soo; Park, Whui Jung; Lee, Hyuk; Kim, Seong Hwan; Park, SangYoun
- Issue Date
- 10-Jul-2014
- Publisher
- ELSEVIER IRELAND LTD
- Keywords
- PAK4; HTS; Protein kinase; Cancer; Drug discovery; X-ray crystallography
- Citation
- CANCER LETTERS, v.349, no.1, pp.45 - 50
- Journal Title
- CANCER LETTERS
- Volume
- 349
- Number
- 1
- Start Page
- 45
- End Page
- 50
- ISSN
- 0304-3835
- 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-yflethyl)-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. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
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Related Researcher
- Park, Sang Youn
- College of Natural Sciences (Department of Bioinformatics & Life Science)