A new study demonstrates how the combination of DNA-encoded libraries (DELs) and NanoBRET Target Engagement technology can accelerate early-stage drug discovery. Reported in Cell Chemical Biology, researchers from Promega Corporation and WuXi AppTec generated new chemical probes from molecules identified through a DEL screen. This research opens new opportunities to develop novel NanoBRET Target Engagement Assays aimed at many understudied classes of proteins, rapidly accelerating “hit to lead” efforts in identifying new potential therapeutics.
Generating Novel Chemical Probes from DELs
DELs are increasingly popular tools used to rapidly screen billions of molecules for early-stage drug discovery. Each molecule is tagged with a short DNA “barcode” that can be used to identify those that successfully bind to a given target. In the Cell Chemical Biology paper, scientists from Promega and WuXi AppTec aimed to develop new chemical probes using molecules selected from these massive pools. These probes would be used in a NanoBRET Target Engagement Assay, a tool for studying the interaction between a chemical compound and its target protein in live cells.
The authors screened 16.8 billion compounds from WuXi AppTec’s 41 established DELs against aurora kinase A, a protein implicated in the invasive growth of certain cancers. They identified two representative “hits” that bound to the target and developed a method to replace the DNA barcode of each “hit” with a fluorophore. The fluorophore is responsible for the light signal generated in a NanoBRET assay in live human cells. The team found that this new probe could be used effectively to characterize novel inhibitors targeting aurora kinase A, providing critical engagement characteristics such as affinity, selectivity and cellular permeability.
“It was very clever of the authors to appreciate that the DEL read-out not only identified a chemical binder for a protein, but also a place to attach a tracer,” says Aled Edwards, Chief Executive of the Structural Genomics Consortium, a public-private partnership that develops open-access chemical probes to support drug discovery and development. “One can only imagine what could be if there were DEL hits for all human proteins.”
Accelerating Drug Discovery
The authors demonstrate that DELs can benefit chemical biologists who require verification of live cell target engagement for their protein of interest. This is particularly beneficial for understudied protein classes that may not have existing chemical probes. Additionally, they note that the NanoBRET assays help drug discovery researchers accelerate their workflow by providing data used to identify the most promising leads.
They conclude, “Our findings support that DEL-derived BRET probes facilitate prioritization of not only the chemical matter identified from the DEL but may also serve as general live-cell screening tools for surveying broader chemotypic diversity at the target of interest.”
Read the open access paper, “DELs enable the development of BRET probes for target engagement studies in cells”.
About Promega Corporation
Promega Corporation is a leader in providing innovative solutions and technical support to the life sciences industry. The company’s portfolio of over 4,000 products supports a range of life science work across areas such as cell biology; DNA, RNA and protein analysis; drug development; human identification and molecular diagnostics. These tools and technologies have grown in their application over the last 45 years and are used today by scientists and technicians in labs for academic and government research, forensics, pharmaceuticals, clinical diagnostics and agricultural and environmental testing. Promega is headquartered in Madison, WI, USA with branches in 16 countries and over 50 global distributors.