title: Small molecules that allosterically inhibit p21-activated kinase activity by binding to the regulatory p21-binding domain.
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.
authors.affiliation: Research Institute and Quality Management Team, NanoPharm Corp., Jincheon-gun, Korea.
authors.forename: Duk-Joong
authors.initials: DJ
authors.lastname: Kim
authors.affiliation: Division of Planning and Research, Korea National Institute of Health, KCDC, Osong Health Technology Administration Complex, Cheongju, Korea.
authors.forename: Chang-Ki
authors.initials: CK
authors.lastname: Choi
authors.affiliation: Livestock Products Standard Division, Food Standard Planning Office, Food Safety Policy Bureau, Ministry of Food and Drug Safety, Osong Health Technology Administration Complex, Cheongju, Korea.
authors.forename: Chan-Soo
authors.initials: CS
authors.lastname: Lee
authors.affiliation: Division of Medical Science Knowledge Management, Center of Biomedical Sciences, Korea National Institutes of Health, Osong Health Technology Administration Complex, Cheongju, Korea.
authors.forename: Mee-Hee
authors.initials: MH
authors.lastname: Park
authors.affiliation: Department of Chemistry, Yanbian University, Yanji, China.
authors.forename: Xizhe
authors.initials: X
authors.lastname: Tian
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Korea.
authors.forename: Nam Doo
authors.initials: ND
authors.lastname: Kim
authors.affiliation: Green Chemistry Division, Korea Research Institute of Chemical Technology, Daejeon, Korea.
authors.forename: Kee-In
authors.initials: KI
authors.lastname: Lee
authors.affiliation: Green Chemistry Division, Korea Research Institute of Chemical Technology, Daejeon, Korea.
authors.forename: Joong-Kwon
authors.initials: JK
authors.lastname: Choi
authors.affiliation: Green Chemistry Division, Korea Research Institute of Chemical Technology, Daejeon, Korea.
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Ahn
authors.affiliation: Department of Biochemistry, College of Medicine and Medical Research Center, Chungbuk National University, Cheongju, Korea.
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Shin
authors.affiliation: Center for Biofunctional Molecules, Department of Chemistry, Yonsei University, Seoul, Korea.
authors.forename: Injae
authors.initials: I
authors.lastname: Shin
authors.affiliation: Department of Biochemistry, College of Medicine and Medical Research Center, Chungbuk National University, Cheongju, Korea.
authors.forename: Eung-Gook
authors.initials: EG
authors.lastname: Kim
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D002460:Cell Line; D055808:Drug Discovery / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*
chemical_list: D007527:Isoenzymes; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D054462:p21-Activated Kinases; D020764:cdc42 GTP-Binding Protein