Senior Principal Scientific Researcher Genentech, California, United States
DNA-encoded library technology (DELT) is a powerful screening platform for the fast and efficient identification of novel chemical matter from ultra-large compound collections in a relatively simple and fast in vitro-based affinity selection experiment (= screen) against today’s most challenging therapeutic targets in biomedical research.
In analogy to antibody phage display technology, DELibrary construction relies on the physical linkage of the phenotype with its genotype: specifically, DNA-encoded chemical libraries are synthesized from chemical building blocks (BBs) in a “split-and-pool” fashion or by other combinatorial means followed by a unique encoding step with DNA oligonucleotides for each BB or reaction type resulting in an exponential growth of library size (m x n → split sizes), while starting from an initial set of m + n BBs. The DNA tags serve as amplifiable and readable identity barcodes of each library member enabling multiplexed deconvolution of the chemical structure by next-generation sequencing (NGS) after elution of binders (= hits) from the target of interest.
Roche has been one of the early adopters of DELT within the pharmaceutical industry, and we are continuously advancing all aspects of the technology. We are now employing DELT on a routine basis at multiple stages of our small-molecule lead discovery process and across all disease areas. In particular, the platform has become an important pillar for ligandability and tractability studies and successive prioritization of therapeutic targets in the early phase of drug discovery programs, as well as for the generation of important tool compounds, and first and foremost, for the rapid delivery of chemical starting points for our small-molecule medicinal chemistry programs. A case study presented here is using DELT to target a key component of autophagic response, ATG8 or LC3. LC3 is required for the elongation and maturation of the autophagosome and functions as an adaptor protein to recruit specific cargo for degradation. Incorporating DELT in our lead finding led to the discovery of novel ligands against this challenging target.