Getting higher-quality hits out of DNA-encoded libraries

DNA-encoded library developers are getting savvier about extracting the most promising hits

DNA-encoded libraries are quickly surpassing traditional high throughput screens as industry’s first stop for hit generation. Now, developers are taking the technology up a notch to get more tractable hits in the output.

DNA-encoded library (DEL) screens blow conventional high throughput screening techniques out of the water when it comes to library size and diversity, enabling screening of millions more compounds without sacrificing time or cost.

The libraries are created through combinatorial chemistry using sets of DNA-tagged chemical building blocks. Each compound can be easily identified by reading its attached tag, then re-synthesized without the tag for validation studies.

The promise of using such large libraries is more shots on goal per target protein, which is particularly important for notoriously difficult targets.

Finding useful hits in the libraries moved from theory to reality when GlaxoSmithKline plc., a pioneer in the technology, brought at least two compounds with DEL origins into the clinic and advanced one of them, RIPK1 inhibitor GSK2982772, into Phase II testing in 2016. GSK did not respond to interview requests.

The inhibitor “attracted attention as it illustrated the potential of DEL technology to find truly

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