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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}chmcc.org.

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Rac1 targeting suppresses p53 deficiency-mediated lymphomagenesis.
E. E. Bosco, W. Ni, L. Wang, F. Guo, J. F. Johnson, and Y. Zheng (2010)
Blood 115, 3320-3328
   Abstract »    Full Text »    PDF »
Activation of Rac1 Is Closely Related to Androgen-Independent Cell Proliferation of Prostate Cancer Cells Both in Vitro and in Vivo.
T. Kobayashi, T. Inoue, Y. Shimizu, N. Terada, A. Maeno, Y. Kajita, T. Yamasaki, T. Kamba, Y. Toda, Y. Mikami, et al. (2010)
Mol. Endocrinol. 24, 722-734
   Abstract »    Full Text »    PDF »
Rac1-mediated NADPH oxidase release of OFormula regulates epithelial sodium channel activity in the alveolar epithelium.
Y. Takemura, P. Goodson, H. F. Bao, L. Jain, and M. N. Helms (2010)
Am J Physiol Lung Cell Mol Physiol 298, L509-L520
   Abstract »    Full Text »    PDF »
Rho GTPase Cdc42 is essential for human T-cell development.
K. Smits, V. Iannucci, V. Stove, P. Van Hauwe, E. Naessens, P. J. Meuwissen, K. K. Arien, M. Bentahir, J. Plum, and B. Verhasselt (2010)
Haematologica 95, 367-375
   Abstract »    Full Text »    PDF »
Rho GTPases in hematopoiesis and hemopathies.
J. C. Mulloy, J. A. Cancelas, M.-D. Filippi, T. A. Kalfa, F. Guo, and Y. Zheng (2010)
Blood 115, 936-947
   Abstract »    Full Text »    PDF »
Role of host cell polarity and leading edge properties in Pseudomonas type III secretion.
D. R. Bridge, M. J. Novotny, E. R. Moore, and J. C. Olson (2010)
Microbiology 156, 356-373
   Abstract »    Full Text »    PDF »
Rac1 and Rac2 GTPases are necessary for early erythropoietic expansion in the bone marrow but not in the spleen.
T. A. Kalfa, S. Pushkaran, X. Zhang, J. F. Johnson, D. Pan, D. Daria, H. Geiger, J. A. Cancelas, D. A. Williams, and Y. Zheng (2010)
Haematologica 95, 27-35
   Abstract »    Full Text »    PDF »
Identification of a Small GTPase Inhibitor Using a High-Throughput Flow Cytometry Bead-Based Multiplex Assay.
Z. Surviladze, A. Waller, Y. Wu, E. Romero, B. S. Edwards, A. Wandinger-Ness, and L. A. Sklar (2010)
J Biomol Screen 15, 10-20
   Abstract »    Full Text »    PDF »
A distinctive role of the leukotriene B4 receptor BLT1 in osteoclastic activity during bone loss.
H. Hikiji, S. Ishii, T. Yokomizo, T. Takato, and T. Shimizu (2009)
PNAS 106, 21294-21299
   Abstract »    Full Text »    PDF »
Regulation of Cross-linked Actin Network (CLAN) Formation in Human Trabecular Meshwork (HTM) Cells by Convergence of Distinct {beta}1 and {beta}3 Integrin Pathways.
M. S. Filla, M. K. Schwinn, N. Sheibani, P. L. Kaufman, and D. M. Peters (2009)
Invest. Ophthalmol. Vis. Sci. 50, 5723-5731
   Abstract »    Full Text »    PDF »
PTP{micro} suppresses glioma cell migration and dispersal.
A. M. Burgoyne, J. M. Palomo, P. J. Phillips-Mason, S. M. Burden-Gulley, D. L. Major, A. Zaremba, S. Robinson, A. E. Sloan, M. A. Vogelbaum, R. H. Miller, et al. (2009)
Neuro Oncology 11, 767-778
   Abstract »    Full Text »    PDF »
Rac1 Is Required for Cardiomyocyte Apoptosis During Hyperglycemia.
E. Shen, Y. Li, Y. Li, L. Shan, H. Zhu, Q. Feng, J. M. O. Arnold, and T. Peng (2009)
Diabetes 58, 2386-2395
   Abstract »    Full Text »    PDF »
Review: In Vitro Models for the Study of Early Human Embryo-Endometrium Interactions.
G. Teklenburg and N. S. Macklon (2009)
Reproductive Sciences 16, 811-818
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{beta}- and {gamma}-cytoplasmic actins display distinct distribution and functional diversity.
V. Dugina, I. Zwaenepoel, G. Gabbiani, S. Clement, and C. Chaponnier (2009)
J. Cell Sci. 122, 2980-2988
   Abstract »    Full Text »    PDF »
Effects of Platelet-Derived Growth Factor on Aqueous Humor Dynamics.
E. Syriani, G. Cuesto, E. Abad, T. Pelaez, A. Gual, J. Pintor, M. Morales, and X. Gasull (2009)
Invest. Ophthalmol. Vis. Sci. 50, 3833-3839
   Abstract »    Full Text »    PDF »
Rac1 Signaling Modulates BCL-6-Mediated Repression of Gene Transcription.
P. Barros, P. Jordan, and P. Matos (2009)
Mol. Cell. Biol. 29, 4156-4166
   Abstract »    Full Text »    PDF »
RhoA and Rac1 GTPases play major and differential roles in stromal cell-derived factor-1-induced cell adhesion and chemotaxis in multiple myeloma.
A. K. Azab, F. Azab, S. Blotta, C. M. Pitsillides, B. Thompson, J. M. Runnels, A. M. Roccaro, H. T. Ngo, M. R. Melhem, A. Sacco, et al. (2009)
Blood 114, 619-629
   Abstract »    Full Text »    PDF »
Breast Cancer Migration and Invasion Depend on Proteasome Degradation of Regulator of G-Protein Signaling 4.
Y. Xie, D. W. Wolff, T. Wei, B. Wang, C. Deng, J. K. Kirui, H. Jiang, J. Qin, P. W. Abel, and Y. Tu (2009)
Cancer Res. 69, 5743-5751
   Abstract »    Full Text »    PDF »
Different Rho GTPase-dependent signaling pathways initiate sequential steps in the consolidation of long-term potentiation.
C. S. Rex, L. Y. Chen, A. Sharma, J. Liu, A. H. Babayan, C. M. Gall, and G. Lynch (2009)
J. Cell Biol. 186, 85-97
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Immunomodulatory drugs reorganize cytoskeleton by modulating Rho GTPases.
Y. Xu, J. Li, G. D. Ferguson, F. Mercurio, G. Khambatta, L. Morrison, A. Lopez-Girona, L. G. Corral, D. R. Webb, B. L. Bennett, et al. (2009)
Blood 114, 338-345
   Abstract »    Full Text »    PDF »
Unraveling a novel Rac1-mediated signaling pathway that regulates cofilin dephosphorylation and secretion in thrombin-stimulated platelets.
D. Pandey, P. Goyal, S. Dwivedi, and W. Siess (2009)
Blood 114, 415-424
   Abstract »    Full Text »    PDF »
Rac1 contributes to trastuzumab resistance of breast cancer cells: Rac1 as a potential therapeutic target for the treatment of trastuzumab-resistant breast cancer.
M. Dokmanovic, D. S. Hirsch, Y. Shen, and W. J. Wu (2009)
Mol. Cancer Ther. 8, 1557-1569
   Abstract »    Full Text »    PDF »
An Adaptor Role for Cytoplasmic Sam68 in Modulating Src Activity during Cell Polarization.
M.-E. Huot, C. M. Brown, N. Lamarche-Vane, and S. Richard (2009)
Mol. Cell. Biol. 29, 1933-1943
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E4orf1 Limits the Oncolytic Potential of the E1B-55K Deletion Mutant Adenovirus.
M. A. Thomas, R. S. Broughton, F. D. Goodrum, and D. A. Ornelles (2009)
J. Virol. 83, 2406-2416
   Abstract »    Full Text »    PDF »

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