Small molecules that allosterically inhibit p21-activated kinase activity by binding to the regulatory p21-binding domain

Duk Joong Kim, Chang Ki Choi, Chan Soo Lee, Mee Hee Park, Xizhe Tian, Nam Doo Kim, Kee In Lee, Joong Kwon Choi, Jin Hee Ahn, Eun Young Shin, Injae Shin, Eung Gook Kim

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)e229
JournalExperimental & molecular medicine
Volume48
DOIs
Publication statusPublished - 2016 Apr 29

Fingerprint

p21-Activated Kinases
Molecules
Cells
rho GTP-Binding Proteins
Deregulation
Cell proliferation
Nervous System Diseases
Actins
Cell Survival
Screening
Enzyme-Linked Immunosorbent Assay
Cell Proliferation

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this

Kim, Duk Joong ; Choi, Chang Ki ; Lee, Chan Soo ; Park, Mee Hee ; Tian, Xizhe ; Kim, Nam Doo ; Lee, Kee In ; Choi, Joong Kwon ; Ahn, Jin Hee ; Shin, Eun Young ; Shin, Injae ; Kim, Eung Gook. / Small molecules that allosterically inhibit p21-activated kinase activity by binding to the regulatory p21-binding domain. In: Experimental & molecular medicine. 2016 ; Vol. 48. pp. e229.
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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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Kim, DJ, Choi, CK, Lee, CS, Park, MH, Tian, X, Kim, ND, Lee, KI, Choi, JK, Ahn, JH, Shin, EY, Shin, I & Kim, EG 2016, 'Small molecules that allosterically inhibit p21-activated kinase activity by binding to the regulatory p21-binding domain', Experimental & molecular medicine, vol. 48, pp. e229. https://doi.org/10.1038/emm.2016.13

Small molecules that allosterically inhibit p21-activated kinase activity by binding to the regulatory p21-binding domain. / Kim, Duk Joong; Choi, Chang Ki; Lee, Chan Soo; Park, Mee Hee; Tian, Xizhe; Kim, Nam Doo; Lee, Kee In; Choi, Joong Kwon; Ahn, Jin Hee; Shin, Eun Young; Shin, Injae; Kim, Eung Gook.

In: Experimental & molecular medicine, Vol. 48, 29.04.2016, p. e229.

Research output: Contribution to journalArticle

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AU - Choi, Chang Ki

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AU - Park, Mee Hee

AU - Tian, Xizhe

AU - Kim, Nam Doo

AU - Lee, Kee In

AU - Choi, Joong Kwon

AU - Ahn, Jin Hee

AU - Shin, Eun Young

AU - Shin, Injae

AU - Kim, Eung Gook

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