Abstract B094: The dual Rac/Cdc42 inhibitor MBQ-167 and derivatives as anticancer compounds
Authors: Castillo-PIchardo Linette , Del Mar Maldonado Maria , Ruiz-Calderon Jean , Rodriguez-Orengo Jose F. , Hernandez Eliud , Vlaar Cornelis , Dharmawardhane Flanagan Surangani F. 
Published: August 2018

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.