Abstract B094: The dual Rac/Cdc42 inhibitor MBQ-167 and derivatives as anticancer compounds (2018)

Abstract Metastatic disease lacks effective treatments, and remains the primary cause of mortality from epithelial cancers. The Rho family GTPases Rac and Cdc42 and their downstream effector p21-activated kinase (PAK) are pivotal regulators of metastatic cancer cell migration and invasion; thus, overexpression of Rac/Cdc42/PAK has been correlated with reduced patient survival in breast, gastric, and lung cancer. Our studies on the efficacy and pharmacokinetics of the Rac inhibitor EHop-016 (US patents # 8,884,006 B2; 9,278,956B1) validated the development of Rac and Cdc42 inhibitors as anti-metastatic cancer therapeutics. To improve the pharmacologic utility of EHop-016, structural derivatives were screened for enhanced efficacy and bioavailability. We recently identified a dual Rac and Cdc42 inhibitor, MetaBloq(MBQ)-167, which inhibits Rac and Cdc42 activation with IC50s of 103 nM for Rac inhibition and 78 nM for Cdc42 inhibition. Moreover, MBQ-167 is specific to cancer cells that have undergone epithelial-to-mesenchymal transition (EMT), but not epithelial cancer cells or noncancer cells. In metastatic cancer cells, MBQ-167 induces a unique phenotype of loss in cell polarity, cell surface actin extensions, and cell-substrate attachments to undergo anoikis (apoptosis due to inadequate cell-matrix interactions). In vivo, MBQ-167 inhibits HER2 type mammary tumor growth and metastasis in immunocompromised mice by ~90-100% (Humphries-Bickley et al., Mol Cancer Ther 2017; patent applications US 15/499532, PCT/US17/29921). In this study, we have further tested the pharmacokinetics and utility of MBQ-167 in additional models of cancer and screened MBQ-167 derivatives for their utility as Rac/Cdc42 inhibitors. Similar to the results with HER2 type breast cancer, in severe combined immunodeficiency (SCID) mice with mammary fat pad tumors from the triple-negative MDA-MB-231 human breast cancer cell line, the effect of MBQ-167 saturated at 1 mg/kg BW with a 80% reduction in tumor growth and a 100% reduction in metastasis. In gastric cancer, MBQ-167 reduced the viability of metastatic NCI-N87 gastric cancer cells, induced anoikis without affecting the AGS nonmetastatic gastric cancer cells, and inhibited tumor growth in SCID mice. We have screened a range of MBQ-167 derivatives for cell viability and the “anoikis” phenotype and isolated 4 compounds that reduced breast cancer cell viability with GI50s in the nM range. From this screen, MBQ-14 acts similar to MBQ-167, and thus is considered to be a viable inhibitor for further investigation. We have developed a quantitative method for identifying MBQ-167 and MBQ-14 from mouse plasma using ultra-performance convergence chromatography (UPC2)/MS/MS, and find that MBQ-167 is bioavailable in mouse plasma with a half-life of ~4h following oral or intraperitoneal administration. Overall our data demonstrate the utility of further developing MBQ-167 and derivatives as anti-metastatic cancer therapeutics. Citation Format: Linette Castillo-PIchardo, Maria Del Mar Maldonado, Jean Ruiz-Calderon, Jose F. Rodriguez-Orengo, Eliud Hernandez, Cornelis Vlaar, Surangani F. Dharmawardhane Flanagan. The dual Rac/Cdc42 inhibitor MBQ-167 and derivatives as anticancer compounds [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B094.