Navigation Links
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 in theory block cancer-fueling proteins without causing unwanted toxicity to healthy cells.

The challenge is to design a chemical structure that can attach to appropriate binding sites on a given target enzyme. Usually, only proteins with sufficiently deep hydrophobic pockets are considered "druggable." In their paper, Zheng and his colleagues said this "significantly limits the scope of the drug discovery effort." The surface area of many G-proteins, including RhoA, is mostly spherical and lacks obvious binding pockets.

Using computer drug design and high-throughput molecular screening, Zheng and his colleagues looked for molecular structures capable of blocking G-protein Rho GEFs. They came up with a structure that in computer-based tests appeared to work. The result was Y16 and derivatives that bind to a critical junction site of an enzyme called LARG (which stands for leukemia-associated Rho guanine nucleotide exchange factor). The compound prevents the LARG enzyme from activating RhoA.

Computer tests showed that by blocking LARG, Y16 suppressed the activation of the RhoA cell signaling and downstream molecular events that fuel cancer growth. These computer tests were subsequently verified by laboratory experiments. The degree of suppression was based on the dosage used by researchers.

This suppression was amplified significantly when Y16 was used with Rhosin/G04, which the investigators previously have shown also targets RhoA. Used independently, Y16 and Rhosin/G04 reduced RhoA cell signaling activity by about 50 percent. Used together, the compounds could work synergistically to inhibit RhoA activity and proliferative potential in breast cancer cells, where RhoA signaling is often hyperactive, the researchers said.

When tested on healthy mammary cells not undergoing cancerous transformation, Y16 and Rhosin/G04 did not affect cell function.

The researchers cautioned that an extensive amount of additional research and verification will be needed before determining if Y16 and Rhosin/G04 could be used in clinical settings with human patients.


'/>"/>

Contact: Nick Miller
nicholas.miller@cchmc.org
513-803-6035
Cincinnati Children's Hospital Medical Center
Source:Eurekalert

Related medicine news :

1. Researchers discover mutations linked to relapse of childhood leukemia
2. Moffitt Cancer Center researchers develop automated breast density test linked to cancer risk
3. Leading researchers warn of brain drain as scientists struggle to find funding
4. Researchers Identify Involuntary Tobacco Smoke Exposure in Boston Public Housing Authority Residents with Salivary Cotinine Testing from Salimetrics.
5. Researchers help confirm value of flow-diverting device for most challenging aneurysms
6. Researchers improve medical units to reduce nursing fatigue, cut costs
7. Researchers find gene that turns up effect of chemotherapy
8. Israeli researchers to participate in European Commission flagship
9. Tumor cells engineer acidity to drive cell invasion, Moffitt Cancer Center researchers say
10. Researchers say its time to treat anemia seriously
11. Rush researchers studying stem cell therapy to repair damaged knee cartilage
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:10/12/2017)... , ... October 12, 2017 , ... ... Hair Restoration, has recently contributed a medical article to the newly revamped ... Dr. Mohebi’s article spotlights the hair transplant procedure known as Follicular Unit ...
(Date:10/12/2017)... Washington, D.C. (PRWEB) , ... October 12, 2017 , ... ... of their peers in Washington, D.C., for the 49th Congress of the International ... Ph.D ., Vice President of the Center for Cancer and Blood Disorders ...
(Date:10/12/2017)... GRAND RAPIDS, Mich. (PRWEB) , ... October 12, ... ... OnSite Wellness, has been named one of Michigan’s 2017 Best and Brightest in ... Best and Brightest in Wellness® awards program on Friday, Oct. 20 from 7:30 ...
(Date:10/12/2017)... ... 12, 2017 , ... In the United States, single-family home ... states—like New York, New Jersey, Massachusetts, Texas, Virginia, Connecticut, and California—the average is ... low property-tax rates, which contributes to the relatively lower cost of living in ...
(Date:10/12/2017)... D.C. (PRWEB) , ... October 12, 2017 , ... ... Cal Dining at the University of California Berkeley, and other leading institutions in ... the buying power of institutions to change the way animals are raised for ...
Breaking Medicine News(10 mins):
(Date:9/28/2017)... -- Hill-Rom Holdings, Inc. (NYSE: HRC), will host its ... on Friday, November 3, 2017, beginning at 7:00 a.m. ... 8:30 a.m. (CDT) / 9:30 a.m. (EDT). ... and guidance for 2018, Hill-Rom executives will also highlight ... and long-range financial outlook through 2020. ...
(Date:9/25/2017)... AMSTERDAM , Sept. 25, 2017   ... Trial Master File solutions, today—from the IQPC Trial ... Amsterdam , NL)—announced that EastHORN Clinical Services ... its clinical programs and TMF management. EastHORN, a ... Montrium,s eTMF platform to increase transparency to enable ...
(Date:9/22/2017)... DIEGO , Sept. 22, 2017 AVACEN ... medical device is now successfully helping those with the ... Fibromyalgia diagnosed Amanda in Essex, ... dressed and washing my hair, experiencing no sleep at ... in painful spasm… I cannot recommend [the AVACEN 100] ...
Breaking Medicine Technology: