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M6 Metabolite Contributes to the Efficacy of the Rac/Cdc42 Inhibitor MBQ-167 in Metastatic Breast Cancer
Nilmary Grafals-Ruiz1, Julia I Medina1, Jessica Colon Gonzalez1
1Department of Biochemistry, School of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico.
Abstract:
Metastasis remains a major challenge in cancer treatment because of the lack of effective targeted therapies. MBQ-167, a first-in-class dual Rac/Cdc42 inhibitor currently in a phase I clinical trial, has demonstrated promising activity in preclinical breast cancer models by reducing tumor burden and preventing metastasis. To characterize its metabolism, we conducted liver microsome assays and identified several MBQ-167 metabolites. Of these, M6 was the primary metabolite from dog and human plasma following oral administration of MBQ-167. The M6cpharmacokinetics profile parallels that of MBQ-167 in human plasma from patients with advanced breast cancer enrolled in the clinical trial. In metastatic breast cancer cell lines (HER2-BM, MDA-MB-231, and MDA-MB-468), M6 exhibited minimal effects on cell viability and apoptosis but strongly inhibited Rac1 activation without affecting Cdc42 activation. M6 also inhibited phosphorylation of group 1 p21-activated kinases (PAK) more effectively than MBQ-167 and significantly reduced breast cancer cell migration in wound healing and Transwell assays. In vivo studies with immunocompromised mice bearing HER2-BM tumors demonstrated that M6 inhibits tumor growth and metastasis to the lungs, livers, and kidneys by ∼90%, comparable with MBQ-167. These findings suggest that M6 exhibits potent anticancer properties both in vitro and in vivo, potentially contributing to the sustained efficacy of MBQ-167 in metastatic breast cancer.
Insights
The primary metabolite of MBQ-167, M6, shows potent anticancer effects by inhibiting Rac1 activation and significantly reducing metastasis in preclinical models. M6
Area of Science:
- Oncology
- Pharmacology
- Cancer Biology
Background:
- Metastasis is a significant challenge in cancer treatment, lacking effective targeted therapies.
- MBQ-167, a dual Rac/Cdc42 inhibitor in Phase 1 trials, shows preclinical efficacy against breast cancer metastasis.
- Characterizing MBQ-167's metabolism is crucial for understanding its therapeutic potential.
Purpose of the Study:
- To identify and characterize the metabolites of MBQ-167.
- To evaluate the in vitro and in vivo anticancer activity of the primary metabolite, M6.
- To determine M6's mechanism of action in metastatic breast cancer cells.
Main Methods:
- Liver microsome assays and plasma analysis to identify MBQ-167 metabolites.
- In vitro assays using metastatic breast cancer cell lines to assess M6's effects on cell viability, apoptosis, Rac1/Cdc42 activation, and cell migration.
- In vivo studies in immunocompromised mice bearing HER2-BM tumors to evaluate M6's impact on tumor growth and metastasis.
Main Results:
- M6 was identified as the primary metabolite of MBQ-167 in dog and human plasma, with parallel pharmacokinetics.
- M6 potently inhibited Rac1 activation and phosphorylation of Group 1 p21-activated kinases (PAKs) in cancer cells.
- M6 significantly reduced breast cancer cell migration and inhibited tumor growth and metastasis by approximately 90% in vivo.
Conclusions:
- M6 exhibits potent anticancer properties, inhibiting Rac1 activation and significantly reducing metastasis.
- M6's efficacy in vitro and in vivo suggests it contributes to MBQ-167's sustained therapeutic effect in metastatic breast cancer.
- Further investigation of M6 as a therapeutic agent is warranted for metastatic breast cancer treatment.
