Novel theory slows cancer growth

A group of scientists from the University of Colorado Cancer Center (UCCC) has used computer modelling technology to examine the structure of the Ral protein in its inactive form, looking specifically for changes in its structure as the protein becomes active.

According to researchers, when active, Ral can drive tumour growth and metastasis in several human cancers including pancreatic, prostate, lung, colon and bladder.

“When you want to keep an alligator from biting you, you can tie its mouth shut. We took another approach

UCCC director Dan Theodorescu

In research published in the journal Nature, scientists used a novel approach to target the activation of 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, director of the UCCC and the study’s senior author.

Researchers discovered that inactive Ral has a cavity that disappears when the protein becomes active. This was the so-called ’mouth’ and now research team needed the ’stick’.

To discover the stick, researchers used a computer software to effectively dock 500,000 compounds in the Ral cavity, which resulted in 88 candidate small molecules that might bind to inactive Ral and prevent its activation.

Laboratory testing evaluated the compounds’ abilities to slow the growth of human cancer cells in suspension - a proxy for metastasis. One molecule, RBC8 proved most successful in this regard, the researchers said.

To refine the working molecule, the UCCC team synthesized derivatives of RBC8 and compared these derivatives to the parent molecule, finding the compound BQU57 relatively effective.

The researchers then moved to test human lung cancer cell models in mice, with the major question being whether cells in an animal model would take up the BQU57 in a way that allowed the compound to eventually be a potential drug in cancer patients.

According to researchers, just hours after initial dosing, the drug had slowed the growth of the lung cancer tumours in mice.

Analysis showed that BQU57 had stopped the activation of Ral in treated tumours, Theodorescu said.

“We still need to optimise these compounds and then characterise 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 said.

“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.”