Novel Small Molecule Inhibits Metastatic Breast Cancer

Background

In an endeavor to develop novel more potent Rac inhibitors with possible clinical applications, the present invention uses NSC23766 as a lead structure for the design of compounds with 2-3 times enhanced potency.

Thus, the present invention reports the identification and characterization of the biological activity of EHop-016, a novel NSC23766 derivative that inhibits Rac1 100-fold more effectively than the parent compound.

Technology Overview

The compound EHop-016, with an IC50 of 1.1 .mu.M, is a 100-fold more efficient inhibitor of Rac activity than NSC23766. EHop-016 is specific for Rac1 and Rac3 at concentrations .ltoreq.5 mM. At higher concentrations, EHop-016 inhibits the close homolog Cdc42. In MDA-MB-435 cells, EHop-016 (.ltoreq.5mM) inhibits the association of the Rac-GEF Vav2 with a nucleotide-free Rac1(G15A), which has a high affinity for activated GEFs.

EHop-016 is an effective Rac-specific inhibitor at low micromolar concentrations. EHop-016 substantially inhibits Vav2 interaction with Rac, Rac-activated PAK1, lamellipodia formation, and cell migration. At concentrations above 5 .mu.M, EHop-016 also inhibits Cdc42 activity and cell viability.

Benefits

EHop-016 does not affect the association of the Rac-GEF Tiam-1 with Rac1(G15A) at similar concentrations. EHop-016 also inhibits the Rac activity of MDA-MB-231 metastatic breast cancer cells and reduces Rac-directed lamellipodia formation in both cell lines. EHop-016 decreases Rac-downstream effects of p21-activated kinase (PAK)1 activity and directed migration of metastatic cancer cells. At low concentrations (<5 .mu.M), EHop-016 does not affect cell viability.

Applications

Since Rac/PAK activity is central to cancer cell migration and invasion, EHop-016 appears to be a promising candidate for further development as a pharmacological inhibitor of Rac activity in metastatic cancer cells. In addition, EHop-016 could prove to be a valuable, more potent probe for the study of Rac‑regulated cellular processes.

Montalvo‑Ortiz, BL et al (2012). Journal of Biological Chemistry; April 12, 2012; 287 (16): 13228‑38.

Opportunity

Non‑exclusive license as research tool.

Research support for in vivo experiments leading to preclinical studies.

Exclusive or non‑exclusive license for drug development, which can include research support for in vivo experiments leading to preclinical studies.