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Researchers use new molecular inhibitors to successfully hit difficult cancer target
Date:2/5/2013

CINCINNATI 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.

Scientists report online Feb. 4 in PNAS Early Edition the rational design of a small-molecule inhibitor they call Y16. In laboratory tests, the inhibitor helped stop the spread of cultured human breast cancer cells, especially when it was used with another compound known as Rhosin/G04.

The study was conducted by researchers in the Cancer and Blood Diseases Institute at Cincinnati Children's Hospital Medical Center, who developed both of the small-molecule inhibitors.

"We are using the findings from this study to refine our compounds and test them on mouse models of Acute Myeloid Leukemia and certain metastatic tumors especially breast cancer, where the target pathway of this lead inhibitor is hyperactive," said Yi Zheng, lead investigator and director of Experimental Hematology/Cancer Biology at Cincinnati Children's.

Y16 and Rhosin/G04 appear to successfully target G-protein mediated Rho guanine nucleotide exchange factors (GEFs), which are part of the Rho GTPase complex of cell signaling proteins. Specifically, the compounds inhibit cell signaling that activates part of the protein complex involving a well-known enzyme, RhoA.

Under normal circumstances, the Rho GTPase complex helps maintain a delicate biological balance in regulating cell structure and function, including proliferation and movement. When the complex becomes dysfunctional, it can cause the hyper-activation of invasive cell growth and cancer.

Small molecule inhibitors are tiny organic compounds that attach to proteins to keep them from binding with other proteins. The intent is to block the activation of harmful biological pathways such as aberrant Rho activity that fuel disease. Used in a dose dependent manner, these compounds can
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Contact: Nick Miller
nicholas.miller@cchmc.org
513-803-6035
Cincinnati Children's Hospital Medical Center
Source:Eurekalert

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