EHop-016 - CAS 1380432-32-5
Catalog number:
1380432-32-5
Category:
Inhibitor
Not Intended for Therapeutic Use. For research use only.
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Targets:
Small GTPase
Description:
EHop-016 is a novel potent and selective inhibitor of RAC. EHop-016 inhibits Rac activity in the MDA-MB-435 metastatic cancer cells that overexpress Rac and exhibits high endogenous Rac activity. The IC(50) of 1.1 μM for Rac inhibition by EHop-016 is ~ 100-fold lower than for NSC23766. EHop-016 is specific for Rac1 and Rac3 at concentrations of < 5 μM. At higher concentrations, EHop-016 inhibits the close homolog Cdc42. EHop-016 also inhibits the Rac activity of MDA-MB-231 metastatic breast cancer cells and reduces Rac-directed lamellipodia formation in both cell lines. EHop-016 decreases Rac downstream effects of PAK1 (p21-activated kinase 1) activity and directed migration of metastatic cancer cells. EHop-016 holds promise as a targeted therapeutic agent for the treatment of metastatic cancers with high Rac activity.
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Purity:
0.98
Appearance:
Solid powder
Synonyms:
EHop-016; EHop016; EHop 016; EHOP-016; EHOP016; EHOP 016
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1.Development of EHop-016: a small molecule inhibitor of Rac.
Dharmawardhane S1, Hernandez E2, Vlaar C2. Enzymes. 2013;33 Pt A:117-46. doi: 10.1016/B978-0-12-416749-0.00006-3. Epub 2013 Aug 8.
The Rac inhibitor EHop-016 was developed as a compound with the potential to inhibit cancer metastasis. Inhibition of the first step of metastasis, migration, is an important strategy for metastasis prevention. The small GTPase Rac acts as a pivotal binary switch that is turned "on" by guanine nucleotide exchange factors (GEFs) via a myriad of cell surface receptors, to regulate cancer cell migration, survival, and proliferation. Unlike the related GTPase Ras, Racs are not usually mutated, but overexpressed or overactivated in cancer. Therefore, a rational Rac inhibitor should block the activation of Rac by its upstream effectors, GEFs, and the Rac inhibitor NSC23766 was developed using this rationale. However, this compound is ineffective at inhibiting the elevated Rac activity of metastatic breast cancer cells. Therefore, a panel of small molecule compounds were derived from NSC23766 and screened for Rac activity inhibition in metastatic cancer cells.
2.Pharmacokinetics of Rac inhibitor EHop-016 in mice by ultra-performance liquid chromatography tandem mass spectrometry.
Humphries-Bickley T1, Castillo-Pichardo L2, Corujo-Carro F3, Duconge J4, Hernandez-O'Farrill E4, Vlaar C4, Rodriguez-Orengo JF5, Cubano L6, Dharmawardhane S7. J Chromatogr B Analyt Technol Biomed Life Sci. 2015 Feb 15;981-982:19-26. doi: 10.1016/j.jchromb.2014.12.021. Epub 2015 Jan 2.
The Rho GTPase Rac is an important regulator of cancer cell migration and invasion; processes required for metastatic progression. We previously characterized the small molecule EHop-016 as a novel Rac inhibitor in metastatic breast cancer cells and recently found that EHop-016 was effective at reducing tumor growth in nude mice at 25 mg/kg bodyweight (BW). The purpose of this study was to compare the pharmacokinetics and bioavailability of EHop-016 at different dosages in a single dose input scheme (10, 20 and 40 mg/kg BW) following intraperitoneal (IP) and oral gavage (PO) administration to nude mice. We developed and validated a rapid and sensitive method for the quantitation of EHop-016 in mouse plasma by ultra high performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry (UPLC/MS/MS). Separation was carried out on an Agilent Poroshell 120 EC-C18 column (3.0 mm × 50 mm) using organic and aqueous mobile phases.
3.The Rac Inhibitor EHop-016 Inhibits Mammary Tumor Growth and Metastasis in a Nude Mouse Model.
Castillo-Pichardo L1, Humphries-Bickley T2, De La Parra C2, Forestier-Roman I3, Martinez-Ferrer M3, Hernandez E3, Vlaar C3, Ferrer-Acosta Y4, Washington AV4, Cubano LA5, Rodriguez-Orengo J2, Dharmawardhane S2. Transl Oncol. 2014 Oct 24;7(5):546-55. doi: 10.1016/j.tranon.2014.07.004. eCollection 2014.
Metastatic disease still lacks effective treatments, and remains the primary cause of cancer mortality. Therefore, there is a critical need to develop better strategies to inhibit metastatic cancer. The Rho family GTPase Rac is an ideal target for anti-metastatic cancer therapy, because Rac is a key molecular switch that is activated by a myriad of cell surface receptors to promote cancer cell migration/invasion and survival. Previously, we reported the design and development of EHop-016, a small molecule compound, which inhibits Rac activity of metastatic cancer cells with an IC50 of 1 μM. EHop-016 also inhibits the activity of the Rac downstream effector p21-activated kinase (PAK), lamellipodia extension, and cell migration in metastatic cancer cells. Herein, we tested the efficacy of EHop-016 in a nude mouse model of experimental metastasis, where EHop-016 administration at 25 mg/kg body weight (BW) significantly reduced mammary fat pad tumor growth, metastasis, and angiogenesis.
4.Characterization of EHop-016, novel small molecule inhibitor of Rac GTPase.
Montalvo-Ortiz BL1, Castillo-Pichardo L, Hernández E, Humphries-Bickley T, De la Mota-Peynado A, Cubano LA, Vlaar CP, Dharmawardhane S. J Biol Chem. 2012 Apr 13;287(16):13228-38. doi: 10.1074/jbc.M111.334524. Epub 2012 Mar 1.
The Rho GTPase Rac regulates actin cytoskeleton reorganization to form cell surface extensions (lamellipodia) required for cell migration/invasion during cancer metastasis. Rac hyperactivation and overexpression are associated with aggressive cancers; thus, interference of the interaction of Rac with its direct upstream activators, guanine nucleotide exchange factors (GEFs), is a viable strategy for inhibiting Rac activity. We synthesized EHop-016, a novel inhibitor of Rac activity, based on the structure of the established Rac/Rac GEF inhibitor NSC23766. Herein, we demonstrate that EHop-016 inhibits Rac activity in the MDA-MB-435 metastatic cancer cells that overexpress Rac and exhibits high endogenous Rac activity. The IC(50) of 1.1 μM for Rac inhibition by EHop-016 is ∼100-fold lower than for NSC23766. EHop-016 is specific for Rac1 and Rac3 at concentrations of ≤5 μM. At higher concentrations, EHop-016 inhibits the close homolog Cdc42.
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