Assay Development and Screening

The use of DNA Encoded Library Technology to identify hits for less tractable targets

• SR

  Stephen Rees, PhD

  VP Discovery Biology
  AstraZeneca

Over the last decade there has been increasing application of DNA Encoded Library (DEL) technology to complement traditional high throughput screening for hit discovery. DNA Encoded Libraries consist of hundreds of millions of molecules synthesised on a DNA tag, such that the structure of the small molecule is genetically encoded by the sequence of the tagged DNA. These libraries are tested against molecular targets in an affinity based selection method. Through the use of such libraries it is possible to test huge numbers of small molecules without incurring the costs of creating a traditional small molecule library and without the automation infrastructure requirements to house and test such compounds. It is the rapid advancement in Next Generation Sequencing technologies that has enabled the creation of this screening paradigm, the ability to mine screening data in depth and has reduced the costs of screening. DEL technology has been adopted by many organisations including AstraZeneca. In partnership with X-Chem we have screened over 40 targets using this screening paradigm. In this presentation I will describe the principles of the DEL platform, and how AstraZeneca has applied this platform as part of our integrated hit discovery strategy, providing examples of the identification of hit series for less tractable targets, and the use of the DEL platform to identify novel binding sites on target proteins.