Characterization of EHop-016, Novel Small Molecule Inhibitor of Rac GTPase

Montalvo-Ortiz, Brenda L.; Castillo‐Pichardo, Linette; Hernández, Eliud; Humphries-Bickley, Tessa; Mota-Peynado, Alina De La; Cubano, Luis A.; Vlaar, Cornelis P.; Dharmawardhane, Suranganie

doi:10.1074/jbc.m111.334524

Cited by 190 publications

(240 citation statements)

References 83 publications

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“…EHop-016, which inhibits Rac GEF interaction and has 100-fold higher specificity than the established Rac inhibitor NSC23766 (Montalvo-Ortiz et al, 2012), was obtained from Millipore. The details of plasmids and RNA interference are described in the supplementary Materials and Methods.…”

Section: Animalsmentioning

confidence: 99%

Novel role of Rac-Mid1 signaling in medial cerebellar development

et al. 2017

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Rac signaling impacts a relatively large number of downstream targets; however, few studies have established an association between Rac pathways and pathological conditions. In the present study, we generated mice with double knockout of Rac1 and Rac3 (Atoh1-Cre;Rac1 flox/flox ;Rac3 −/− ) in cerebellar granule neurons (CGNs). We observed impaired tangential migration at E16.5, as well as numerous apoptotic CGNs at the deepest layer of the external granule layer (EGL) in the medial cerebellum of Atoh1-Cre; Rac1 flox/flox ;Rac3 −/− mice at P8. Atoh1-Cre;Rac1 flox/flox ;Rac3CGNs differentiated normally until expression of p27 kip1 and NeuN in the deep EGL at P5. Primary CGNs and cerebellar microexplants from Atoh1-Cre;Rac1 flox/flox ;Rac3 −/− mice exhibited impaired neuritogenesis, which was more apparent in Map2-positive dendrites. Such findings suggest that impaired tangential migration and final differentiation of CGNs have resulted in decreased cerebellum size and agenesis of the medial internal granule layer, respectively. Furthermore, Rac depleted/deleted cells exhibited decreased levels of Mid1 and impaired mTORC1 signaling. Mid1 depletion in CGNs produced mild impairments in neuritogenesis and reductions in mTORC1 signaling. Thus, a novel Rac-signaling pathway (Rac1-Mid1-mTORC1) may be involved in medial cerebellar development.

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Section: Animalsmentioning

confidence: 99%

Novel role of Rac-Mid1 signaling in medial cerebellar development

et al. 2017

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“…Alternatively, Rac1 and/or Rac2 alone may play only a modest role in KITD814V-induced transformation. To test these possibilities and to more precisely identify the consequence(s) of interfering with the function of GEFs and Rac in KITD814V-induced transformation, we used a novel Rac inhibitor, EHop-016, which is a derivative of NSC23766 and inhibits Rac 100-fold more efficiently than NSC23766 in breast cancer cell lines (18). As seen in Figure 4, A and B, KITD816V-bearing SM patient-derived HMC1.2 cells, as well as KITD816V-and AML1-ETO-bearing Kasumi-1 cells derived from an AML patient, demonstrated a significant reduction in the growth of these cells in the presence of EHop-016 at drug concentrations that were significantly less (~50-fold in some cases) than those of NSC23766.…”

Section: Figurementioning

confidence: 99%

“…While reasonable, an alternate explanation may involve a lack of robust involvement of Trio and Tiam1 in KITD814V-induced transformation. Therefore, in an effort to assess whether Rac GTPase could be targeted more efficiently in KIT oncogene-bearing cells, we used a newly described Rac inhibitor, EHop-016 (18). This drug is a derivative of NSC23766 and inhibits Rac 100-fold more efficiently relative to the parental compound (18).…”

Section: Figurementioning

confidence: 99%

“…NSC23766 inhibits the activation of Rac by interfering with the binding of GEFs Tiam1 and Trio (17). More recently, Ortiz et al described a novel Rac inhibitor, EHop-016, which is derived on the basis of the structure of NSC23766 and inhibits the activation of Rac with a substantially lower IC 50 compared with NSC23766 (18). How these two drugs impact the relative growth of KITD814V-bearing cells and whether they equally inhibit the activation of Rac1 versus Rac2 in these cells has never been explored.…”

Section: Introductionmentioning

confidence: 99%

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Pak and Rac GTPases promote oncogenic KIT–induced neoplasms

Martin¹,

Mali²,

Ma³

et al. 2013

J. Clin. Invest.

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“…Compared with FAK inhibitors, Rac1 inhibitors were under development. 35,36 Hopefully, the development of these inhibitors may provide us a new therapeutic option for both efficacious and nontoxic treatment of OSCC in the near future. In summary, we have demonstrated the elevated FAK expression and its pY397 in OSCC tumors and cell lines.…”

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confidence: 99%

Tyrosine 397 phosphorylation is critical for FAK-promoted Rac1 activation and invasive properties in oral squamous cell carcinoma cells

Yuan

2016

Laboratory Investigation

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Oral squamous cell carcinoma (OSCC) is a common cancer worldwide. Despite advances in diagnosis and therapy, treatment options for patients with metastatic OSCC are few, due in part to the limited understanding of the molecular events involved in the invasion and metastasis of OSCC. In this study, we investigated the expression of focal adhesion kinase (FAK) and its tyrosine 397 phosphorylation (pY397) in the tissue specimens of OSCC. The roles of pY397 in regulating the activities of Rac1 and cortactin and the invasive properties of OSCC cells were further determined. Results from immunohistochemical analyses in 9 benign, 19 premalignant, and 19 malignant oral tissues showed that the immunoreactivity of FAK was observed in 5 benign (56%), 19 premalignant (100%), and 18 malignant tissues (95%), whereas the immunoreactivity of pY397 was only found in 1 of 9 (11%) benign lesions but was observed in 9 premalignant (47%) and 12 malignant (63%) lesions. Compared with the low-invading SCC4 cells, the high-invading OECM-1 cells exhibited higher levels of FAK expression and pY397, correlating with higher levels of GTP-bound Rac1 and cortactin phosphorylation. Manipulation of FAK expression or Y397 phosphorylation in SCC4, FaDu, OECM-1, or HSC-3 cells regulated their Rac1 activities and invasive properties. Furthermore, treatment of NSC23766, a Rac1-specific inhibitor, in OECM-1 and HSC-3 cells led to reduced invasive properties. Nevertheless, knockdown of FAK expression or suppression of pY397 had no effect on the cortactin activity in OECM-1 cells. The data collectively suggest that pY397 plays critical roles in the FAK-promoted Rac1 activation and invasive properties in OSCC cells. Thus, the inhibition of FAK phosphorylation at Y397 or Rac1 activity can serve as a therapeutic strategy for treating patients with metastatic OSCC. Oral squamous cell carcinoma (OSCC) is the most common malignancy occurring in the oral cavity that usually arises from the buccal mucosa and tongue. During the tumor progression, OSCC cells gradually spread and invade to neighboring tissues, including the nasal cavity or the maxillary facial structures, and eventually metastasize to neck lymph nodes and distant organs. 1 Similar to other malignant diseases, tumor metastasis is a great challenge for the treatment of OSCC. This notion is supported by the fact that only 50% of diagnosed OSCC patients can survive for 5 years, and this is mainly because OSCC patients continue to die from tumor relapse at regional or distant sites. 2 Despite advances in diagnosis and therapy in past decades, the promising strategy for treating patients with metastatic OSCC is still underdeveloped, due in part to the limited understanding of the molecular events involved in invasion and metastasis of OSCC. The underlying molecular basis of OSCC metastasis deserves intensive study.Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase and functionally involves the regulatory processes of multiple cellular events, including adhesion, migration, invasion, prolifer...

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Characterization of EHop-016, Novel Small Molecule Inhibitor of Rac GTPase

Cited by 190 publications

References 83 publications

Novel role of Rac-Mid1 signaling in medial cerebellar development

Novel role of Rac-Mid1 signaling in medial cerebellar development

Pak and Rac GTPases promote oncogenic KIT–induced neoplasms

Tyrosine 397 phosphorylation is critical for FAK-promoted Rac1 activation and invasive properties in oral squamous cell carcinoma cells

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