Efficacy of Rac and Cdc42 Inhibitor MBQ-167 in Triple-negative Breast Cancer
Ailed Cruz-Collazo, Jean F Ruiz-Calderon, Hector Picon, Luis D Borrero-Garcia, Irmaris Lopez, Linette Castillo-Pichardo, Maria Del Mar Maldonado, Jorge Duconge, Julia I Medina, Marvin J Bayro, Eliud Hernández-O'Farrill, Cornelis P Vlaar, Suranganie Dharmawardhane, Ailed Cruz-Collazo, Jean F Ruiz-Calderon, Hector Picon, Luis D Borrero-Garcia, Irmaris Lopez, Linette Castillo-Pichardo, Maria Del Mar Maldonado, Jorge Duconge, Julia I Medina, Marvin J Bayro, Eliud Hernández-O'Farrill, Cornelis P Vlaar, Suranganie Dharmawardhane
Abstract
Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer, with a high predisposition for locally invasive and metastatic cancer. With the objective to reduce cancer metastasis, we developed small molecule inhibitors to target the drivers of metastasis, the Rho GTPases Rac and Cdc42. Of these, MBQ-167 inhibits both Rac and Cdc42 with IC50s of 103 and 78 nmol/L, respectively; and consequently, inhibits p21-activated kinase (PAK) signaling, metastatic cancer cell proliferation, migration, and mammosphere growth; induces cell-cycle arrest and apoptosis; and decreases HER2-type mammary fatpad tumor growth and metastasis (Humphries-Bickley and colleagues, 2017). Herein, we used nuclear magnetic resonance to show that MBQ-167 directly interacts with Rac1 to displace specific amino acids, and consequently inhibits Rac.GTP loading and viability in TNBC cell lines. Phosphokinome arrays in the MDA-MB-231 human TNBC cells show that phosphorylation status of kinases independent of the Rac/Cdc42/PAK pathway are not significantly changed following 200 nmol/L MBQ-167 treatment. Western blotting shows that initial increases in phospho-c-Jun and phospho-CREB in response to MBQ-167 are not sustained with prolonged exposure, as also confirmed by a decrease in their transcriptional targets. MBQ-167 inhibits tumor growth, and spontaneous and experimental metastasis in immunocompromised (human TNBC) and immunocompetent (mouse TNBC) models. Moreover, per oral administration of MBQ-167 at 100 mg/kg body weight is not toxic to immunocompetent BALB/c mice and has a half-life of 4.6 hours in plasma. These results highlight the specificity, potency, and bioavailability of MBQ-167, and support its clinical potential as a TNBC therapeutic.
Conflict of interest statement
Conflict of interest: LBG is a current, and HP is a former, employee of MBQ Pharma, Inc. SD, LCP, EH, and CPV and own stock at MBQ Pharma, Inc., which has licensed patents US 9,981,980, US10,392,396 and international patents related to PCT/US2017/029921 relevant to this work from the University of Puerto Rico.
©2021 American Association for Cancer Research.
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Source: PubMed