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KMID : 0620920160480040004
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Experimental & Molecular Medicine
2016 Volume.48 No. 4 p.4 ~ p.4
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Small molecules that allosterically inhibit p21-activated kinase activity by binding to the regulatory p21-binding domain
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Kim Duk-Joong
Choi Chang-Ki
Lee Chan-Soo
Park Mee-Hee
Xizhe Tian
Kim Nam-Doo
Lee Kee-In
Choi Joong-Kwon
Ahn Jin-Hee
Shin Eun-Young
Shin In-jae
Kim Eung-Gook
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Abstract
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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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KEYWORD
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