Features Partner Sites Information LinkXpress
Sign In
Demo Company

Virtual Screening Identifies New Low Molecular Weight Anticancer Drug Candidates

By BiotechDaily International staff writers
Posted on 21 Feb 2013
Print article
Computer modeling and high throughput molecular screening were used to identify low molecular weight compounds capable of blocking the activity of procancerous signaling molecules called G-protein mediated Rho guanine nucleotide exchange factors (GEFs).

GEFs have been implicated in several human diseases including cancer, but finding suitable drugs to block their activity has proven difficult due to a lack of distinctive formational features in the three-dimensional structure of these molecules. Investigators at Cincinnati Children's Hospital Medical Center (OH, USA) have approached this problem from a new direction.

They reported in the February 4, 2013, online edition of the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS) that they had virtually screened chemicals that fit into a surface groove of the DH-PH domain of LARG (leukemia-associated Rho guanine nucleotide exchange factor), a G-protein-regulated Rho GEF involved in RhoA activation, and had followed up the virtual tests with validations in biochemical assays. This methodology allowed them to identify a class of chemical inhibitors represented by Y16 that was active in specifically inhibiting LARG binding to RhoA.

RhoA (Ras homolog gene family, member A) is a small GTPase protein known to regulate the actin cytoskeleton in the formation of stress fibers. This protein is essential for the signaling function of the Rho GTPase complex. Previous studies have shown that in breast cancer increased RhoA activity stimulated cancer cell invasiveness and spreading, while RhoA deficiency suppressed cancer growth and progression. In addition to its role in breast cancer, imbalance in Rho GTPase activity has been implicated in other human diseases, including various cancers and neurological disorders.

The suppressive effect of Y16 was significantly amplified by using the compound together with Rhosin/G04, a drug previously shown to target RhoA. The combination of Y16 and Rhosin/G04 did not interfere with other cellular signaling functions.

"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 senior author Dr. Yi Zheng, professor of pediatrics at Cincinnati Children's Hospital Medical Center.

Related Links:
Cincinnati Children's Hospital Medical Center

Print article



view channel
Image: Left: Green actin fibers create architecture of the cell. Right: With cytochalasin D added, actin fibers disband and reform in the nuclei (Photo courtesy of the University of North Carolina).

Actin in the Nucleus Triggers a Process That Directs Stem Cells to Mature into Bone

A team of cell biologists has discovered why treatment of mesenchymal stem cells (MSCs) with the mycotoxin cytochalasin D directs them to mature into bone cells (osteoblasts) rather than into fat cells... Read more


view channel

Molecular Light Shed on “Dark” Cellular Receptors

Scientists have created a new research tool to help find homes for orphan cell-surface receptors, toward better understanding of cell signaling, developing new therapeutics, and determining causes of drug side-effects. The approach may be broadly useful for discovering interactions of orphan receptors with endogenous, naturally... Read more


view channel

Purchase of Biopharmaceutical Company Will Boost Development of Nitroxyl-Based Cardiovascular Disease Drugs

A major international biopharmaceutical company has announced the acquisition of a private biotech company that specializes in the development of drugs for treatment of cardiovascular disease. Bristol-Myers Squibb Co. (New York, NY, USA) has initiated the process to buy Cardioxyl Pharmaceuticals Inc. (Chapel Hill, NC, USA).... Read more
Copyright © 2000-2015 Globetech Media. All rights reserved.