Exp Mol Med.
2016 Apr;48(4):e229. 10.1038/emm.2016.13.
Small molecules that allosterically inhibit p21-activated kinase activity by binding to the regulatory p21-binding domain
- Affiliations
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- 1Research Institute and Quality Management Team, NanoPharm Corp., Jincheon-gun, Korea.
- 2Division of Planning and Research, Korea National Institute of Health, KCDC, Osong Health Technology Administration Complex, Cheongju, Korea.
- 3Livestock Products Standard Division, Food Standard Planning Office, Food Safety Policy Bureau, Ministry of Food and Drug Safety, Osong Health Technology Administration Complex, Cheongju, Korea.
- 4Division of Medical Science Knowledge Management, Center of Biomedical Sciences, Korea National Institutes of Health, Osong Health Technology Administration Complex, Cheongju, Korea.
- 5Department of Chemistry, Yanbian University, Yanji, China.
- 6New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Korea.
- 7Green Chemistry Division, Korea Research Institute of Chemical Technology, Daejeon, Korea.
- 8Department of Biochemistry, College of Medicine and Medical Research Center, Chungbuk National University, Cheongju, Korea. injae@yonsei.ac.kr
- 9Center for Biofunctional Molecules, Department of Chemistry, Yonsei University, Seoul, Korea. egkim@chungbuk.ac.kr
- KMID: 2361516
- DOI: http://doi.org/10.1038/emm.2016.13
Abstract
- p21-activated kinases (PAKs) are key regulators of actin dynamics, cell proliferation and cell survival. Deregulation of PAK activity contributes to the pathogenesis of various human diseases, including cancer and neurological disorders. Using an ELISA-based screening protocol, we identified naphtho(hydro)quinone-based small molecules that allosterically inhibit PAK activity. These molecules interfere with the interactions between the p21-binding domain (PBD) of PAK1 and Rho GTPases by binding to the PBD. Importantly, they inhibit the activity of full-length PAKs and are selective for PAK1 and PAK3 in vitro and in living cells. These compounds may potentially be useful for determining the details of the PAK signaling pathway and may also be used as lead molecules in the development of more selective and potent PAK inhibitors.
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