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Ref Type Journal Article
PMID (28450422)
Authors Humphries-Bickley T, Castillo-Pichardo L, Hernandez-O'Farrill E, Borrero-Garcia LD, Forestier-Roman I, Gerena Y, Blanco M, Rivera-Robles MJ, Rodriguez-Medina JR, Cubano LA, Vlaar CP, Dharmawardhane S
Title Characterization of a Dual Rac/Cdc42 Inhibitor MBQ-167 in Metastatic Cancer.
Journal Molecular cancer therapeutics
Vol 16
Issue 5
Date 2017 May
URL
Abstract Text The Rho GTPases Rac (Ras-related C3 botulinum toxin substrate) and Cdc42 (cell division control protein 42 homolog) regulate cell functions governing cancer malignancy, including cell polarity, migration, and cell-cycle progression. Accordingly, our recently developed Rac inhibitor EHop-016 (IC50, 1,100 nmol/L) inhibits cancer cell migration and viability and reduces tumor growth, metastasis, and angiogenesis in vivo Herein, we describe MBQ-167, which inhibits Rac and Cdc42 with IC50 values of 103 and 78 nmol/L, respectively, in metastatic breast cancer cells. Consequently, MBQ-167 significantly decreases Rac and Cdc42 downstream effector p21-activated kinase (PAK) signaling and the activity of STAT3, without affecting Rho, MAPK, or Akt activities. MBQ-167 also inhibits breast cancer cell migration, viability, and mammosphere formation. Moreover, MBQ-167 affects cancer cells that have undergone epithelial-to-mesenchymal transition by a loss of cell polarity and inhibition of cell surface actin-based extensions to ultimately result in detachment from the substratum. Prolonged incubation (120 hours) in MBQ-167 decreases metastatic cancer cell viability with a GI50 of approximately 130 nmol/L, without affecting noncancer mammary epithelial cells. The loss in cancer cell viability is due to MBQ-167-mediated G2-M cell-cycle arrest and subsequent apoptosis, especially of the detached cells. In vivo, MBQ-167 inhibits mammary tumor growth and metastasis in immunocompromised mice by approximately 90%. In conclusion, MBQ-167 is 10× more potent than other currently available Rac/Cdc42 inhibitors and has the potential to be developed as an anticancer drug, as well as a dual inhibitory probe for the study of Rac and Cdc42. Mol Cancer Ther; 16(5); 805-18. ©2017 AACR.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
MBQ-167 MBQ-167 1 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
MBQ-167 MBQ-167 inhibits Rac1 and Cdc42, resulting in decreased downstream signaling, increased cell-cycle arrest, and reduced tumor growth and metastasis (PMID: 28450422).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown breast cancer not applicable MBQ-167 Preclinical - Cell line xenograft Actionable In a preclinical study, MBQ-167 increased cell-cycle arrest and decreased viability and migration of breast cancer cell lines in culture, and reduced tumor growth and metastasis in a breast cancer cell line xenograft model (PMID: 28450422). 28450422