Novel approach identifies highly specific anti-cancer compounds
Researchers at Baylor College of Medicine and Texas Children’s Hospital have identified potent, highly specific compounds that interfere with bromodomain (BD)-containing proteins involved in cancer. The compounds, called BET BD1-inhibitors, are a starting point in the development of potentially more effective anti-cancer drugs with less side effects.
The team reports in the Proceedings of the National Academy of Sciences that the novel approach developed at Baylor’s Center for Drug Discovery (CDD) enables the screening of billions of compounds at once and precisely identifies potent drug-like molecules that bind to the cancer protein of interest. One key advantage of this approach is the price tag — these screens are a fraction of the cost of previous methods. In laboratory experiments with cells, the new BD1-inhibitors had marked anti-leukemic activity.
“BD-containing proteins are implicated in cancer, inflammation, infectious diseases and metabolic disorders and have emerged as potential drug targets in a variety of diseases,” said Dr. Joanna Yi, one of the lead authors and assistant professor of pediatric hematology/oncology at Baylor and Texas Children’s. “Over a decade of research has shown that BD-inhibitors can help control cancer growth; however, when tested in clinical trials some had side effects and limited efficacy, halting further clinical development. This has encouraged our group to search for more effective BD-inhibitors.”
The researchers focused on identifying inhibitors specific for the first bromodomains (BD1) in the bromodomain and extra-terminal (BET) subgroup of human proteins. Recent research has shown that BD1 is very important in driving cancer, the researchers explained.
“To identify novel BD1-inhibitors, we took advantage of an innovative, faster and more cost-effective drug discovery tool called DNA-Encoded Chemistry Technology, which enables us to screen billions of compounds,” said first author Dr. Ram K. Modukuri, a staff scientist in the Department of Pathology & Immunology and the CDD at Baylor.
The more commonly used method for discovering drugs, called high throughput screening, involves screening at most a million compounds in individual test tubes. In contrast, by using DNA-Encoded Chemistry Technology, the team was able to screen 4 billion DNA-encoded molecules all in one test tube against BD1 to find one that would bind to it with high specificity when compared to binding to other bromodomains.
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