Virtual Screening Identifies New Low Molecular Weight Anticancer Drug Candidates

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.

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