M6 Metabolite Contributes to the Efficacy of the Rac/Cdc42 Inhibitor MBQ-167 in Metastatic Breast Cancer.

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.