Researchers from Baylor College of Medicine and Texas Children’s Hospital have identified potent, highly specific compounds that interfere with bromodomain-containing (BD) proteins implicated in cancer. The compounds, called BET BD1 inhibitors, are a stepping stone in the development of potentially more effective cancer drugs with fewer side effects.
Team Reports In Proceedings of the National Academy of Sciences The new approach developed at the Baylor Center for Drug Discovery (CDD) allows screening of billions of compounds simultaneously and precisely identifies potent drug molecules that bind to the cancer protein of interest. Price is one of the main advantages of this approach – these screens are a fraction of the cost of the previous methods. In lab experiments with cells, the new BD1 inhibitors showed anti-leukemic activity.
“BD-containing proteins have been implicated in cancer, inflammation, infectious diseases, and metabolic disorders and have emerged as potential drug targets in various diseases,” said lead author and Associate Professor of Pediatric Hematology and Oncology Joanna Yee. In Baylor, 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 research BD inhibitors.”
The researchers focused on identifying specific inhibitors of early bromodomain (BD1) in a subset of the human bromodomain and peripheral subgroup (BET) proteins. The researchers explained that recent research has shown that BD1 is very important in driving cancer.
The previous author, Dr. Ram K. Modukuri. , a scientist in the Department of Pathology, Immunology and CDD at Baylor.
The most common method used for drug discovery, called high-throughput screening, involves screening at most one million compounds in individual test tubes. By 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 a molecule that binds to it with higher accuracy than it does to other bromod domains.
“DNA-encoded chemistry technology has allowed us to identify CDD-724, a highly selective compound for BD1. It is about 2,000 times more effective at inhibiting BD1 than at inhibiting other human domains, including bromodomain II (BD2) from the BET subgroup,” said Modukuri. .
How does DNA-encoded chemistry work?
Corresponding author Dr. Martin Matzuk, professor and chair of the Department of Pathology and Immunology and director of the Drug Discovery Center at Baylor, said. “The molecules that ‘stick’ to a protein (in this case BD1) are determined by the sequence of the DNA code associated with it. It’s a rapid drug discovery screen, and our study demonstrates its tremendous potential for finding unique candidates for cancer drugs.”
To better understand why the BD1 inhibitor stands out from other inhibitors, the team collaborated with Dr. Schuel Kim, assistant professor of pharmacology and chemical biology, who is also a member of the CDD and Dan L Duncan Comprehensive Cancer Center at Baylor. . The researchers performed 3D molecular studies to determine the exact location on the BD1 protein to which the BD1 inhibitor binds. They found that the BD1 inhibitor binds to a shallower region of the BD1 protein, which other BD1 inhibitors do not. This finding represents a new opportunity to explore other selective BD1 inhibitors.
“We are looking for highly specific, potent, effective compounds with low side effects that we can bring into the clinic,” said Yi, who is also a CDD member from Baylor and Dan L Duncan Comprehensive Cancer Center. “We are ready to test these compounds in animal models to assess their safety and efficacy, bringing 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, and Nicholas Simmons Stephen S. Palmer, Mingxing Teng, and Damian W. Young are also in this business. The authors are affiliated with Baylor College of Medicine and/or Texas Children’s Hospital.
This work is supported by the Bill & 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 Basic Facilities Support Award from the Cancer Prevention Research Institute of Texas (CPRIT) ) (RP160805). Additional support was provided by National Institutes of Health grants (5K12CA090433-17, R01DK121970, R61HD099995, S10RR25528, S10RR028976, S10OD027000), Alex’s Lemonade Stand Foundation, Curing Kids Cancer Foundation, CURE Childhood Cancer Foundation, and CPRIT (RR00220012).
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