Abstract Metastasis is the leading cause of treatment failure and poor prognosis in cancer patients; however, there are few metastasis targeted therapies. The homologous Rho GTPases Rac and Cdc42 are viable targets in metastatic cancer due to their central role in cancer cell proliferation, viability, survival, migration, and invasion. In cancer, Rac and Cdc42 are not generally mutated but activated by oncogenic guanine nucleotide exchange factors (GEFs), which exchange the GDP for a GTP. We developed the clinical-stage compound MBQ-167, a Rac and Cdc42 inhibitor, as a metastasis inhibitor. CPV-337 is an MBQ-167 derivative that is specific for Rac (Rac1,2, 3, Rac1b) with an IC50 of ∼50nM (i.e., 2X more effective than MBQ-167) in HER2++ breast cancer and an IC50 of 100nM in pancreatic cancer. CPV-337 has a GI50 of 57nM in metastatic breast cancer cells without affecting mammary epithelial cells. In a mouse model of HER2++ breast cancer experimental metastasis, treatment with 5mg/kg CPV-337 resulted in ∼90% reduction in mammary tumor growth and metastasis, to the same extent as 10 mg/kg MBQ-167. The objective herein was to characterize the mechanism by which CPV-337 acts as an anticancer agent. We show that CPV-337 inhibits the phosphorylation of Rac downstream effectors PAK and Cofilin, which regulate actin cytoskeletal structures, such as lamellipodia. A significant reduction of the Rac downstream effector WAVE protein that also regulates the actin cytoskeleton, was also observed following CPV-337 treatment. Accordingly, CPV-337 inhibits lamellipodia formation, invasion, and migration of HER2++ breast cancer cells. To identify the mechanism by which CPV-337 inhibits Rac1, pulldowns were conducted using the Rac1(G15A) nucleotide-free mutant, which has a higher affinity for activated GEFs. Of the GEFs tested, Ect2 (Epithelial Cell Transforming 2) was identified as the major Rac.GEF inhibited by CPV-337. To date there are no known Rac-Ect2 specific inhibitors, despite Ect2 being a critical oncogene that regulates cytokinesis and cell cycle progression. Overexpression of Ect2 in different types of cancer has been associated with poor prognosis and reduced overall survival. Ongoing studies are evaluating the inhibitory mechanism of CPV-337 and its specificity using CRISPR-Cas9 Rac-1 knockout breast cancer cells. In conclusion, CPV-337 is a promising anti breast and pancreatic cancer drug with a unique and specific mechanism of inhibition. Citation Format: Jessica Colon Gonzalez, Nilmary Grafals-Ruiz, Anamaris Torres-Sanchez, Cornelis Vlaar, Suranganie Dharmawardhane. Novel Ect2-Rac inhibitor CPV-337 in breast and pancreatic cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7099.
Gonzalez et al. (Fri,) studied this question.