New approach identifies highly specific anti-cancer compounds

Researchers at 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. Dubbed BET-BD1 inhibitors, the compounds are a starting point for the development of potentially more effective anti-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), enables the screening of billions of compounds at once and accurately identifies effective drug molecules that bind to the cancer protein of interest. One of the main advantages of this approach is the price – these screens cost a fraction of previous methods. In laboratory experiments with cells, the new BD1 inhibitors showed pronounced 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. 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 early bromodomain (BD1) inhibitors in the bromodomain and extraterminal (BET) subset of human proteins. Recent research has shown that BD1 is very important in promoting cancer, the researchers explained.

“To identify novel BD1 inhibitors, we used an innovative, faster, and less expensive drug discovery tool called DNA-Encoded Chemistry Technology, which allows us to screen billions of compounds,” said former author Dr. Ram K Modukuri. , a scientist in Baylor’s Department of Pathology and Immunology and CDD.

The most common drug discovery method, known as 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 enabled us to identify CDD-724, a highly selective compound for BD1. It is approximately 2,000-fold more potent at inhibiting BD1 than at inhibiting other human bromodomains, including the second bromodomain (BD2) of the BET subgroup. ‘ Modukuri said.

How does DNA-encoded chemistry technology work?

“The process of DNA-encoded chemistry technology involves the simultaneous screening of billions of molecules, each labeled with a DNA barcode,” said corresponding author Dr. Martin Matzuk, Professor and Chair of Pathology and Immunology and Director of the Center for Drug Discovery at Baylor. “The molecules that ‘stick’ to the protein (BD1 in this case) are identified by sequencing their attached DNA barcode. It is a rapid drug discovery screening and our study demonstrates its tremendous potential to find unique anticancer drug candidates. . »

To better understand why their BD1 inhibitor differs from other inhibitors, the team sat down 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 in Baylor. . Researchers performed 3D molecular studies to determine the precise site on the BD1 protein to which the BD1 inhibitor binds. They found that the BD1 inhibitor binds to a flat region 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 CDD member of Baylor and the Dan L Duncan Comprehensive Cancer Center. “We are poised 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 for 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).

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