Y16 compound shows early signs of success against breast cancer cells

Early laboratory tests are the first to successfully use an experimental molecular therapy to block a hard-to-target part of a protein complex linked to several types of invasive cancer.

Yi Zheng, PhD, and colleagues from the Cancer and Blood Diseases Institute at Cincinnati Children’s reported results of tests involving a small-molecule inhibitor called Y16 Feb 4 in the online edition of PNAS Early Edition. In these tests, the inhibitor helped stop the spread of cultured human breast cancer cells, especially when used in combination with another compound known as Rhosin/G04.

“We are using the findings from this study to refine our compounds and test them on mouse models of acute myeloid leukemia (AML) and certain metastatic tumors – especially breast cancer, where the target pathway of this lead inhibitor is hyperactive,” says Zheng, lead investigator and director of Experimental Hematology/Cancer Biology at Cincinnati Children’s.

List of ‘druggable’ targets expands

Much more research and verification will be needed before Y16 and Rhosin/G04 can be tested in human clinical trials. However, the latest findings may indicate a way to attack a group of cancer-related proteins that until now had not been considered “druggable.”

Y16 and Rhosin/G04 target G-protein mediated Rho guanine nucleotide exchange factors (GEFs), which are part of the Rho GTPase complex of cell signaling proteins. Under normal circumstances, the Rho GTPase complex helps maintain a delicate biological balance in regulating cell proliferation and movement. When the complex becomes dysfunctional, it can cause hyper-activation of invasive cell growth and cancer.

Compounds could block cancer without harming normal cell functions

Small-molecule inhibitors are tiny organic compounds that attach to proteins to keep them from binding with other proteins. In theory, these types of compounds can block cancer-fueling proteins without causing unwanted toxicity to healthy cells.

The challenge has been to design chemical structures  that can attach to appropriate binding sites. Usually, only proteins with sufficiently deep hydrophobic pockets are considered “druggable.” However, many G-proteins, including RhoA, lack obvious binding pockets.

Using computer drug design and high-throughput molecular screening, Zheng and his colleagues determined that Y16 overcomes the lack of binding pockets by attaching to a critical junction site of an enzyme called LARG (leukemia-associated Rho guanine nucleotide exchange factor).

Reported results.

Read more about Zheng’s research in the latest issue of Research Horizons.