Researchers from Baylor College of Medicine and Texas Children’s Hospital have identified potent and highly specific compounds that interfere with bromodomain (BD)-containing proteins implicated in cancer. The compounds, called BET BD1 inhibitors, are a starting point in the development of potentially more effective cancer drugs with fewer side effects.
The team reports in the Proceedings of the National Academy of Sciences that the new approach developed at Baylor’s Center for Drug Discovery (CDD) allows the screening of billions of compounds at once and accurately identifies potent drug molecules that bind to the cancer protein of interest. One of the main advantages of this approach is the price – 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 various diseases,” said lead author and professor Dr. Joanna Yi. pediatric hematology/oncology assistant. at Baylor and Texas Children’s. “More than 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 clinical development. This encouraged our group to search for BD-inhibitors. »
Researchers focused on identifying specific inhibitors of early 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 leveraged an innovative, faster, and more cost-effective drug discovery tool called DNA-Encoded Chemistry Technology, which allows us to screen billions of compounds,” said the former. author, Dr. Ram K. Modukuri. , a scientist in the Department of Pathology and Immunology and CDD at Baylor.
The most common method used to discover drugs, called high-throughput screening, involves screening at most one million compounds in individual test tubes. In contrast, using DNA-encoded chemistry technology, the team was able to screen 4 billion DNA-encoded molecules in a single test tube against BD1 to find one that would bind to it with high specificity compared to binding to other bromodomains.
“DNA-encoded chemistry technology allowed us to identify CDD-724, a highly selective compound for BD1. It is approximately 2,000 times more effective at inhibiting BD1 than at inhibiting other human bromodomains, including the second bromodomain (BD2) of the BET subgroup. “said Modukuri.
How does DNA-encoded chemistry technology work?
“The process of DNA-encoded chemistry technology involves simultaneous screening of billions of molecules, each labeled with a DNA barcode,” said corresponding author Dr. Martin Matzuk, professor and chair of pathology and of immunology and director of the Center for Drug Discovery at Baylor. “The molecules that ‘stick’ to the protein (in this case BD1) are identified by sequencing their attached DNA barcode. It is a rapid drug discovery screen, and our study demonstrates its enormous potential for finding unique candidates for cancer drugs. . »
To better understand why their BD1 inhibitor stands out from other inhibitors, the team teamed up with Dr. Choel Kim, associate professor of pharmacology and chemical biology, who is also a member of CDD and the Dan L Duncan Comprehensive Cancer Center at Baylor. . The researchers conducted 3D molecular studies to determine the precise location on the BD1 protein to which the BD1 inhibitor binds. They found that the BD1 inhibitor binds to a shallow area of the BD1 protein, which other BD1 inhibitors do not. This discovery represents a new opportunity to explore other selective BD1 inhibitors.
“We are looking for highly specific, potent and effective compounds with reduced side effects that we can bring to the clinic,” said Yi, also a CDD member from Baylor and the Dan L Duncan Comprehensive Cancer Center. “We are ready to test these compounds in animal models to assess their safety and efficacy, which brings us one step closer to clinical trials. »
Zhifeng Yu, Zhi Tan, Hai Minh Ta, Melek Nihan Ucisik, Zhuang Jin, Justin L. Anglin, Kiran L. Sharma, Pranavanand Nyshadham, Feng Li, Kevin Riehle, John C. Faver, Kevin Duong, Sureshbabu Nagarajan, Nicholas Simmons, Stephen S. Palmer, Mingxing Teng, and Damian W. Young also contributed to this work. The authors are affiliated with Baylor College of Medicine and/or Texas Children’s Hospital.
This work is supported by the Bill and Melinda Gates Foundation (INV-001902), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01HD087157), the Welch Foundation (HQ-0042), and a Core Facility Support Award from the Institute of Cancer Prevention Research of Texas (CPRIT) (RP160805). Additional support was provided by NIH grants (5K12CA090433-17, R01DK121970, R61HD099995, S10RR25528, S10RR028976, and S10OD027000), Alex’s Lemonade Stand Foundation, Curing Kids Cancer Foundation, CURE Childhood Cancer Foundation, and CPRIT grants (RR220012 and RR220039).