Characterization of EHT 1864, a Novel Small Molecule Inhibitor of Rac Family Small GTPases

Onesto, Cercina; Shutes, Adam; Picard, Virginie; Schweighoffer, Fabien; Der, Channing J.

doi:10.1016/s0076-6879(07)00409-0

Cited by 101 publications

(94 citation statements)

References 34 publications

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“…This inhibitor has previously been shown to specifically inhibit RAC1, RAC2 and RAC3 activities (Onesto et al, 2008). As shown in Figure 4a, EHT 1864 exhibited a dose dependent inhibition of E2/ERa mediated ERE luciferase activity in MCF-7 cells, with maximal inhibition occurring at 5-10 mM EHT 1864.…”

Section: Knockdown and Inhibition Of Rac3 Block Era Induced Gene Exprmentioning

confidence: 68%

“…Rho-family GTPases are overexpressed in a variety of human tumors and have a wide range of roles throughout the cell, including the regulation of cell migration and adhesion, mitosis, regulation of kinase activity and regulation of transcription factors through cell signaling pathways (Baugher et al, 2005;Onesto et al, 2008). The RAC family of GTPases consists of three members, RAC1, RAC2 and RAC3.…”

Section: Introductionmentioning

confidence: 99%

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RAC3 is a pro-migratory co-activator of ERα

Walker

Zhang

et al. 2011

Oncogene

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Estrogen receptor alpha (ERa) is a ligand-dependent nuclear receptor that is important in breast cancer genesis, behavior and response to hormone-based therapies. A T7 phage display screen against full-length human ERa, coupled with genome-wide exon arrays, was used to identify RAC3 as a putative ERa co-regulator. RAC3 is a Rho family small GTPase that is associated with cytoskeletal rearrangement. We demonstrate a novel role for nuclear RAC3 as an ERa transcriptional activator, with prognostic implications for metastatic disease. Through in vitro and cell-based studies, RAC3 was shown to exist in a GTP-bound state and act as a ligand specific ERa co-activator of E2-induced transcription. Overexpression of RAC3 induced pro-growth and pro-migratory genes that resulted in increased migration of ERapositive breast cancer cells. Chemical inhibition and genetic knockdown of RAC3 antagonized E2-induced cell proliferation, cell migration and ERa mediated gene expression, indicating that RAC3 is necessary for full ERa transcriptional activity. In agreement with the molecular and cellular data, RAC3 overexpression in ERa-positive breast cancers correlated with a significant decrease in recurrence free survival and a significant increase in the odds ratio of metastasis. In conclusion, RAC3 is a novel ERa co-activator that promotes cell migration and has prognostic value for ERa-positive breast cancer metastasis. RAC3 may also be a useful therapeutic target for ERa-positive breast cancers.

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Section: Knockdown and Inhibition Of Rac3 Block Era Induced Gene Exprmentioning

confidence: 68%

Section: Introductionmentioning

confidence: 99%

RAC3 is a pro-migratory co-activator of ERα

Walker

Zhang

et al. 2011

Oncogene

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“…44 More recently, another Rac1 inhibitor (EHT 1864) has been developed which inhibits guanine nucleotide association, thus rendering Rac1 inactive. [45][46][47] The results of this study demonstrate the important roles of Rac1 in NSCLC cell proliferation and migration and compare the effects of Rac1-specific siRNA to that of Rac1 inhibition by NSC23766. One possible mechanism contributing to these multiple roles of Rac1 may be through the Rac1-dependent regulation of NFκB transcriptional activity in NSCLC.…”

Section: Acknowledgmentsmentioning

confidence: 82%

The role of Rac1 in the regulation of NF-kB activity, cell proliferation, and cell migration in non-small cell lung carcinoma

Gastonguay

Berg

Hauser

et al. 2012

Cancer Biology & Therapy

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“…EHT 1864 is known to bind with high affinity to Rac1, Rac1b, Rac2, and with somewhat lower affinity to Rac3. The inhibitor has been suggested to place Rac in an inactive state by promoting the loss of bound guanine nucleotide, rather than interfering with RhoGEF-induced Rac activation, as described for other Rac inhibitors such as NSC23766 (40,41). Fig.…”

Section: R665wmentioning

confidence: 96%

The Phospholipase Cγ2 Mutants R665W and L845F Identified in Ibrutinib-resistant Chronic Lymphocytic Leukemia Patients Are Hypersensitive to the Rho GTPase Rac2 Protein

Walliser

Hermkes

Schade

et al. 2016

Journal of Biological Chemistry

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Mutations in the gene encoding phospholipase C-␥ 2 (PLC␥ 2 ) have been shown to be associated with resistance to targeted therapy of chronic lymphocytic leukemia (CLL) with the Bruton's tyrosine kinase inhibitor ibrutinib. The fact that two of these mutations, R665W and L845F, imparted upon PLC␥ 2 an ϳ2-3-fold ibrutinib-insensitive increase in the concentration of cytosolic Ca 2؉ following ligation of the B cell antigen receptor (BCR) led to the assumption that the two mutants exhibit constitutively enhanced intrinsic activity. Here, we show that the two PLC␥ 2 mutants are strikingly hypersensitive to activation by Rac2 such that even wild-type Rac2 suffices to activate the mutant enzymes upon its introduction into intact cells. Enhanced "basal" activity of PLC␥ 2 in intact cells is shown using the pharmacologic Rac inhibitor EHT 1864 and the PLC␥ 2 F897Q mutation mediating Rac resistance to be caused by Rac-stimulated rather than by constitutively enhanced PLC␥ 2 activity. We suggest that R665W and L845F be referred to as allomorphic rather than hypermorphic mutations of PLCG2. Rerouting of the transmembrane signals emanating from BCR and converging on PLC␥ 2 through Rac in ibrutinib-resistant CLL cells may provide novel drug treatment strategies to overcome ibrutinib resistance mediated by PLCG2 mutations or to prevent its development in ibrutinib-treated CLL patients.Inositol-phospholipid-specific phospholipases C (PLCs) 3 regulate many fundamental functions of normal and neoplastic B cells (1, 2). They catalyze the formation of inositol 1,4,5-trisphosphate (InsP 3 ) and diacylglycerol and, at the same time, decrease the local or general plasma membrane abundance of their substrate, phosphatidylinositol 4,5-bisphosphate (PtdInsP 2 ) (3). Three members of the six mammalian PLC subfamilies, ␤, ␥, ␦, ⑀, , and , play important roles in B cells as follows: PLC␤ 2 , PLC␤ 3 , and PLC␥ 2 . PLC␤ 2 and PLC␤ 3 are important in mediating B cell responses to G-protein-coupled chemokine receptors (4). PLC␥ 2 serves as a key component of the B cell receptor (BCR) signalosome by interacting with cell surface receptor activation, e.g. by antigens (5), cleavage fragments of the third complement component (6), and bacterial, viral, or autoimmunity host DNA (7), and even certain chemokines (8). PLC␥ 2 activation results in InsP 3 -mediated increases in the concentration of free Ca 2ϩ , diacylglycerol-mediated activation of protein kinases C, and changes in transmembrane signaling directly mediated by PtdInsP 2 (9).Several lines of evidence point to an important contribution of enhanced BCR signaling in the pathogenesis, progression, and/or maintenance of B cell leukemias and lymphomas. For example, leukemic B cells of patients with chronic lymphocytic leukemia (CLL) specifically express a restricted immunoglobulin heavy variable (IGHV) gene repertoire, suggesting that CLL development represents an antigen-superantigen-driven process (10). Furthermore, the presence or absence of somatic mutations in rearranged IGHV genes determin...

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Characterization of EHT 1864, a Novel Small Molecule Inhibitor of Rac Family Small GTPases

Cited by 101 publications

References 34 publications

RAC3 is a pro-migratory co-activator of ERα

RAC3 is a pro-migratory co-activator of ERα

The role of Rac1 in the regulation of NF-kB activity, cell proliferation, and cell migration in non-small cell lung carcinoma

The Phospholipase Cγ2 Mutants R665W and L845F Identified in Ibrutinib-resistant Chronic Lymphocytic Leukemia Patients Are Hypersensitive to the Rho GTPase Rac2 Protein

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