Summary:
- Amgen's DNA Encoded Library (DEL) technology links chemical compounds to DNA barcodes, enabling scientists to screen billions of molecules in days instead of decades.
- DEL is being used in various challenging disease areas to develop next-generation small molecules with enhanced specificity and therapeutic potential.
- The technology can identify small molecules such as "glues" that harness the body's biological machinery and inhibit or remove harmful proteins to drive therapeutic effects.
In the early stages of drug discovery, one of the greatest challenges is finding a molecule with the right properties that binds a disease-related target and affects its function. Traditionally, this process involves labor-intensive screening of thousands—or even millions—of compounds, one at a time. Not only is this time consuming and resource-intensive, but many promising compounds remain undiscovered simply because they were not included in the screening library.
Amgen is redefining this search process by leveraging its DNA-Encoded Library (DEL) platform, a transformative technology that enables researchers to simultaneously screen billions of compounds.
"Imagine screening 2 billion molecules against a disease target," said Alex Gouliaev, vice president at Amgen's Research site in Copenhagen, where the DEL technology is based. "With traditional ultra-high-throughput screening, that would take about 50 years. But we can screen 2 billion molecules in one morning and fit them all in one tube, eliminating the need to separate each molecule into individual wells of a plate."
At the core of DEL is a simple yet powerful concept: each small molecule in the library is linked to a unique DNA sequence that serves as a molecular barcode. When the library is exposed to a protein target, compounds that bind the target can be isolated and identified by sequencing their DNA tags. This process allows Amgen scientists to scan an enormous chemical landscape in a single experiment—often billions of compounds at once.
Unlocking New Possibilities with Small Molecule Drug Discovery
Amgen's DEL platform has been designed to be highly modular and adaptive, capable of screening for a wide range of therapeutic targets. For example, DEL technology can help identify potential molecular "glues," compounds that bind molecules together, harnessing the body's own biological machinery to drive a therapeutic effect. This strategy has broad potential applications across various diseases.
The DEL platform is designed to integrate seamlessly with other discovery technologies at Amgen, including structural biology and medicinal chemistry that determine how well a molecule binds its target and help determine whether it has drug-like behavior.
"DEL has fundamentally changed how we discover small-molecule drugs," said Ryan Potts vice president of Research and head of Amgen's Induced-Proximity Platform, a cutting-edge approach in drug discovery that leverages the body's natural mechanisms to target disease-causing molecules. "What's truly exciting is that it allows us to go after targets that were previously considered undruggable—by finding molecules that either directly inhibit a target or induce proximity between two proteins, effectively rewiring cellular pathways."
One clinical candidate to emerge from Amgen's DEL platform is AMG 193, an investigational small molecule inhibitor of PRMT5 (protein arginine methyltransferase 5).
PRMT5 is involved in tumor growth, particularly in cancers missing the MTAP (methylthioadenosine phosphorylase) gene—a vulnerability found in several tumor types. Cancer cells lacking the MTAP gene accumulate high levels of MTA (methylthioadenosine), conditions that are potentially favorable for AMG 193 to bind and inhibit PRMT5. Conversely, AMG 193 is designed to bind much more weakly to PRMT5 in normal cells due to the relative absence of MTA.
Amgen researchers used the DEL platform to find a unique molecule that binds selectively to PRMT5 when MTA is present. They screened close to 100 million molecules with the PRMT5 target proteins and MTA, identifying those that bind tightly. Because each molecule being screened is tagged with DNA, the scientists rapidly identified the bound molecules.
"AMG 193 exemplifies what DEL is capable of," said Margaret Chu-Moyer, vice president of Research and head of the Small Molecule Therapeutic Discovery team. "It began as a single hit in a massive library and evolved into a clinical candidate through an efficient, data-driven optimization process. It's a tangible example of how DEL can shorten timelines and increase the odds of success."
A Strategic Acquisition
In 2019, Amgen acquired Nuevolution, a small company based in Copenhagen known for its DEL technology. The acquisition aimed not only to obtain access to this innovative therapeutic molecule-finding technology but also to integrate a team of expert scientists with substantial experience in constructing and refining libraries of compounds that could speed up molecular screens.
"We spent years perfecting our DEL platform and building one of the world's largest and most diverse collections of chemical fragments," said Gouliaev, who was the former CEO of Nuevolution before joining Amgen. "Joining Amgen meant we could take this technology to the next level—applying it across a broad range of disease areas with the support and scale of a global research organization."
Before Amgen acquired Nuevolution, the company had built one of the world's largest collections of chemical building blocks—about 60,000 in total. These fragments serve as the foundation for designing new compounds, allowing researchers to rapidly generate and test massive molecular libraries. The molecules in the screening library are generated from scratch and are designed to function more like therapeutics than simple small molecules.
By integrating DEL into its broader discovery strategy, Amgen has strengthened its ability to discover and develop next-generation small-molecule therapies – drugs that have the potential to be more selective and effective than ever before.
