扼住癌症生长 z-bo 2020-09-16 363

　　When the protein called Ral is activated, it drives tumor growth and metastasis in several human cancers including pancreatic cancer, prostate cancer, lung cancer, colon cancer, and bladder cancer. Unfortunately, there is currently no drug that can block the activity of Ral.

　　"If you want to prevent the crocodile from biting you, you can tie the crocodile's mouth tightly. We took another approach-put a stick in the crocodile's mouth to keep it open," the senior author of the paper, Said Dr. Dan Theodorescu, director of the University of Colorado Cancer Center and professor of urology and pharmacology.

　　The new research uses some advanced computer models to detect the structure of the Ral protein when it is in an "inactive" state, and specifically investigates the changes in this structure when the protein is "activated". The results show that the "inactivated" Ral has a cavity, which disappears when the protein is activated. This is the "crocodile's mouth", and now Theodorescu and colleagues need a "stick."

　　In order to find the required stick, the researchers used a computer to get 500,000 compounds into this cavity, and found that 88 small candidate molecules can bind to the inactivated Ral and prevent its activation. The researchers then tested these results in human cancer cells, and they used these compounds to treat cancer cells to see which compounds can minimize Ral activation. From this group of compounds, they found a few compounds that are particularly capable of reducing Ral activation in lung cancer cells (extended reading: Nature draws a comprehensive molecular map of lung cancer).

　　Further tests evaluated the ability of these compounds to slow the growth of suspended human cancer cells (representing metastasis). One called RBC8 is the most successful in this regard. In order to further transform this functional molecule, the research team synthesized derivatives of RBC8, and compared these derivatives with the parent molecule, and found that a compound they labeled BQU57 was very effective.

　　Next, the test turned to a mouse human lung cancer cell model. Whether the cells in the animal model will absorb BQU57, making the compound a potential drug for cancer patients is an important question to be answered by this test. In other words, the researchers want to confirm whether the drugs that work in petri dishes also work in animals?

　　As expected, BQU57 entered the tumor tissue a few hours after the administration. And not only did it get into it, the drugs also slowed the growth of these tumors. The results of the analysis showed that BQU57 prevented Ral activation in the treatment of tumors.

　　Theodorescu said: "Before entering the clinic, we still need to optimize these compounds, determine the toxicity characteristics of these drugs in several animal species, and determine their best delivery route, such as oral or intravenous administration. We will This research work is regarded as a valuable first step in the development of a new type of Ral targeted therapy."