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PNAS 101 (20): 7618-7623

Copyright © 2004 by the National Academy of Sciences.

Cell Biology

Rational design and characterization of a Rac GTPase-specific small molecule inhibitor

Yuan Gao *, J. Bradley Dickerson {dagger}, Fukun Guo *, Jie Zheng {dagger}, and Yi Zheng *, {ddagger}

*Division of Experimental Hematology, Children's Hospital Research Foundation, Cincinnati, OH 45229; and {dagger}Department of Structure Biology, St. Jude Children's Research Hospital, Memphis, TN 38105

Edited by Lewis C. Cantley, Harvard Institutes of Medicine, Boston, MA

Accepted for publication March 30, 2004.

Received for publication November 13, 2003.

Abstract: The signaling pathways mediated by Rho family GTPases have been implicated in many aspects of cell biology. The specificity of the pathways is achieved in part by the selective interaction between Dbl family guanine nucleotide exchange factors (GEFs) and their Rho GTPase substrates. Here, we report a first-generation small-molecule inhibitor of Rac GTPase targeting Rac activation by GEF. The chemical compound NSC23766was identified by a structure-based virtual screening of compounds that fit into a surface groove of Rac1 known to be critical for GEF specification. In vitro it could effectively inhibit Rac1 binding and activation by the Rac-specific GEF Trio or Tiam1 in a dose-dependent manner without interfering with the closely related Cdc42 or RhoA binding or activation by their respective GEFs or with Rac1 interaction with BcrGAP or effector PAK1. In cells, it potently blocked serum or platelet-derived growth factor-induced Rac1 activation and lamellipodia formation without affecting the activity of endogenous Cdc42 or RhoA. Moreover, this compound reduced Trio or Tiam1 but not Vav, Lbc, Intersectin, or a constitutively active Rac1 mutant-stimulated cell growth and suppressed Trio, Tiam1, or Ras-induced cell transformation. When applied to human prostate cancer PC-3 cells, it was able to inhibit the proliferation, anchorage-independent growth and invasion phenotypes that require the endogenous Rac1 activity. Thus, NSC23766constitutes a Rac-specific small-molecule inhibitor that could be useful to study the role of Rac in various cellular functions and to reverse tumor cell phenotypes associated with Rac deregulation.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: GEF, guanine nucleotide exchange factor; PDGF, platelet-derived growth factor.

{ddagger} To whom correspondence should be addressed at: Division of Experimental Hematology, Children's Hospital Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229. E-mail: yi.zheng{at}

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One Percent Tenofovir Applied Topically to Humanized BLT Mice and Used According to the CAPRISA 004 Experimental Design Demonstrates Partial Protection from Vaginal HIV Infection, Validating the BLT Model for Evaluation of New Microbicide Candidates.
P. W. Denton, F. Othieno, F. Martinez-Torres, W. Zou, J. F. Krisko, E. Fleming, S. Zein, D. A. Powell, A. Wahl, Y. T. Kwak, et al. (2011)
J. Virol. 85, 7582-7593
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Rhinovirus-Induced Barrier Dysfunction in Polarized Airway Epithelial Cells Is Mediated by NADPH Oxidase 1.
A. T. Comstock, S. Ganesan, A. Chattoraj, A. N. Faris, B. L. Margolis, M. B. Hershenson, and U. S. Sajjan (2011)
J. Virol. 85, 6795-6808
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Guanine nucleotide exchange factor Vav1 regulates perivascular homing and bone marrow retention of hematopoietic stem and progenitor cells.
A. Sanchez-Aguilera, Y.-J. Lee, C. Lo Celso, F. Ferraro, K. Brumme, S. Mondal, C. Kim, A. Dorrance, H. R. Luo, D. T. Scadden, et al. (2011)
PNAS 108, 9607-9612
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ROP GTPases Act with the Receptor-Like Protein PAN1 to Polarize Asymmetric Cell Division in Maize.
J. A. Humphries, Z. Vejlupkova, A. Luo, R. B. Meeley, A. W. Sylvester, J. E. Fowler, and L. G. Smith (2011)
PLANT CELL 23, 2273-2284
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Novel Role of Rac1/WAVE Signaling Mechanism in Regulation of the Epithelial Na+ Channel.
A. V. Karpushev, V. Levchenko, D. V. Ilatovskaya, T. S. Pavlov, and A. Staruschenko (2011)
Hypertension 57, 996-1002
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Targeting p21-activated kinase 1 (PAK1) to induce apoptosis of tumor cells.
C. C. Ong, A. M. Jubb, P. M. Haverty, W. Zhou, V. Tran, T. Truong, H. Turley, T. O'Brien, D. Vucic, A. L. Harris, et al. (2011)
PNAS 108, 7177-7182
   Abstract »    Full Text »    PDF »
An ezrin-rich, rigid uropod-like structure directs movement of amoeboid blebbing cells.
A. Lorentzen, J. Bamber, A. Sadok, I. Elson-Schwab, and C. J. Marshall (2011)
J. Cell Sci. 124, 1256-1267
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Sphingomyelin upregulation in mature neurons contributes to TrkB activity by Rac1 endocytosis.
L. Trovo, P. P. Van Veldhoven, M. G. Martin, and C. G. Dotti (2011)
J. Cell Sci. 124, 1308-1315
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Evidence That the Lipid Phosphatase SHIP-1 Regulates T Lymphocyte Morphology and Motility.
S. J. Harris, R. V. Parry, J. G. Foster, M. D. Blunt, A. Wang, F. Marelli-Berg, J. Westwick, and S. G. Ward (2011)
J. Immunol. 186, 4936-4945
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Follicular Fluid High-Density Lipoprotein-Associated Sphingosine 1-Phosphate (S1P) Promotes Human Granulosa Lutein Cell Migration via S1P Receptor Type 3 and Small G-Protein RAC1.
S. Becker, S. von Otte, H. Robenek, K. Diedrich, and J.-R. Nofer (2011)
Biol Reprod 84, 604-612
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TLR2-dependent pathway of heterologous down-modulation for the CC chemokine receptors 1, 2, and 5 in human blood monocytes.
J. M. Fox, E. Letellier, C. J. Oliphant, and N. Signoret (2011)
Blood 117, 1851-1860
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Enforced hematopoietic cell E- and L-selectin ligand (HCELL) expression primes transendothelial migration of human mesenchymal stem cells.
S. P. Thankamony and R. Sackstein (2011)
PNAS 108, 2258-2263
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Active Rac1 improves pathologic VEGF neovessel architecture and reduces vascular leak: mechanistic similarities with angiopoietin-1.
M. V. Hoang, J. A. Nagy, and D. R. Senger (2011)
Blood 117, 1751-1760
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Deletion of ABCA1 and ABCG1 Impairs Macrophage Migration Because of Increased Rac1 Signaling.
T. A. Pagler, M. Wang, M. Mondal, A. J. Murphy, M. Westerterp, K. J. Moore, F. R. Maxfield, and A. R. Tall (2011)
Circ. Res. 108, 194-200
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Phagocyte-like NADPH oxidase promotes cytokine-induced mitochondrial dysfunction in pancreatic {beta}-cells: evidence for regulation by Rac1.
W. Subasinghe, I. Syed, and A. Kowluru (2011)
Am J Physiol Regulatory Integrative Comp Physiol 300, R12-R20
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The Rac1/JNK pathway is critical for EGFR-dependent barrier formation in human airway epithelial cells.
M. Terakado, Y. Gon, A. Sekiyama, I. Takeshita, Y. Kozu, K. Matsumoto, N. Takahashi, and S. Hashimoto (2011)
Am J Physiol Lung Cell Mol Physiol 300, L56-L63
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Plexin-A4-semaphorin 3A signaling is required for Toll-like receptor- and sepsis-induced cytokine storm.
H. Wen, Y. Lei, S.-Y. Eun, and J. P.-Y. Ting (2010)
J. Exp. Med. 207, 2943-2957
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Aberrant Overexpression of the Rgl2 Ral Small GTPase-specific Guanine Nucleotide Exchange Factor Promotes Pancreatic Cancer Growth through Ral-dependent and Ral-independent Mechanisms.
D. Vigil, T. D. Martin, F. Williams, J. J. Yeh, S. L. Campbell, and C. J. Der (2010)
J. Biol. Chem. 285, 34729-34740
   Abstract »    Full Text »    PDF »

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