The fight against cancer is on. With all the researches that are going on in the area we are finding newer ways of combating it. Dan Theodorescu, MD, PhD, director of the University of Colorado Cancer Center talks about the newly discovered novel drug that could help us in combating cancer. This drug is representative of a class of new drugs, which is active against a major driver of cancer metastasis. The major driver of cancer metastasis we are talking about is Ral. It can drive tumor growth and metastasis several forms of cancer like pancreatic, prostate, lung, colon and bladder. However, the drug that could block is not available. In order to deal with the activation of the Ral protein, a new approach was used.
There are several ways of dealing with a problem. You could deal with it head on and you could find a hack. Dan explains it using a simple example if you want to keep an alligator from biting you, you can tie its mouth. Or you can put a stick in its mouth so that it keeps its mouth open. Dan says they applied the second technique. They carried a study using sophisticated computer model to examine the structure of the inactive form of Ral protein. In particular they were looking for the changes in its structure when its molecule became active. Studies revealed that inactive Ral has a cavity that disappears when it comes active. Dan and team recognized it as the mouth and now they needed to find the stick.
Using the computer, they tried to fit in 500,000 compounds in this cavity of which only 88 seem to fit and might possibly prevent its activation. In the next step, the researchers applied their findings to human cancer cells. They treated them with these compounds to see which of them resulted in reduction of Ral activation. There were a handful of compounds that significantly reduced Ral activation in lung cancer cells. Further tests were carried on the said compounds that evaluated their abilities to reduce the growth of human cancer cells. Thus they found RBC8, which was the most effective molecule in that regard. The team further refined their research and synthesized derivatives of RBC8. They then compared these derivatives to the parent molecule, and found that a compound labeled as BQU57 was quite effective.
The next step in the research process was to test the same in human lung cancer models in mice. The crucial thing to find out here was whether the BQU57 would work the same way as it did in the prior experiment. The good news is the not only the BQU57 entered tumor tissue, the drug was effective in slowing down its growth. Analysis revealed that BQU57 had indeed stopped the activation of Ral in treated tumors.
Dan Theodorescu said that these compounds do need further optimization. They have to characterize these agents for toxicity in various animal species and also need to determine their optimal route of delivery, such as oral or intravenous. Dan Theodorescu, MD, PhD, professor of Urology and Pharmacology, director of the University of Colorado Cancer Center and the study’s senior author have led a multidisciplinary team of investigators from the University of Colorado, Indiana University, the University of Virginia and Yale University. He concluded that they see this work as a valuable first step in the development of a new class of therapeutic agents directed at Ral. Their approach could in principle help in discovering drugs for other proteins driving human disease as well.