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A protein called Ral, in the active state can drive tumor growth and metastasis in several human cancers including pancreatic, prostate, lung, colon and bladder. Unfortunately, drugs that can block the activity of Ral are not yet available. 

A new study describes using a novel approach to target the activation of these Ral proteins.

"When you want to keep an alligator from biting you, you can tie its mouth shut. We took another approach - we put a stick in its mouth to hold it open," said Dan Theodorescu, MD, PhD, professor of Urology and Pharmacology, director of the University of Colorado Cancer Center and the study's senior author, who led a multidisciplinary team of investigators from the University of Colorado, Indiana University, the University of Virginia and Yale University.

The study, using sophisticated computer models, found that the inactive 'Ral' has a cavity that disappears when the protein becomes active. 

Eventually researchers took the findings to human cells and treated these with compounds to see which resulted in the greatest reduction of Ral activation. They found that a derivative of RBC8, dubbed BQU57 had entered the tumor tissue and also slowed the growth of the tumors. 

"We still need to optimize these compounds and then characterize these agents for toxicity in several animal species and determine their optimal route of delivery, such as oral or intravenous before moving to the clinic," Theodorescu added in the press release. "But we see this work as a valuable first step in the development of a novel class of therapeutic agents directed at Ral. The concept of targeting sites on proteins that collapse upon activation, and whose collapse is required for activation, could in principle be used to discover drugs aimed at other proteins driving human disease as well."

The study is published in the journal Nature.