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DEL for
DNA encoded library (DEL) selection has been applied on various target classes and different modalities, yielding ligands progressed into different stages of drug development. In this session, we review the major advantages and potential challenges of DEL selection on diverse targets including PPI, kinases, GPCRs, RNAs and etc., as well as different modalities like covalent ligands and Protein degraders.
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OpenDEL®
OpenDEL® has previously been released by HitGen as a self-serve product in 2015 (https://www.nature.com/articles/d43747-020-00040-4). After several years of evolution, it now contains small molecule DELs with high diversity and drug-like space and helps to increase the possibility of finding potential hits in an efficient and cost-effective manner.
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Novel BRD4 Degrader Discovery using DEL Technology
DEL selection is an affinity-based approach to recognize compounds interacting with the target, including the compounds modulating target function(s) or simply binding to the protein. The architecture of a DNA Encoded Compound is very similar to proteolysis targeting chimeras (PROTAC) as shown in the following figure. Both DEL compound and PROTAC molecule require covalent linkage of two molecules with known attachment points that have minimal impact to the binding.
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Identification of Transferase NAA50 Inhibitors by DEL Selection
The two isomers of the selected compound DEL951-34-888-1668 were synthesized and tested by SPR in the presence of CoA and AcCoA and biochemical assay. The chiral isomer 4a has been found as a very potent inhibitor with improved MW, Ligand Efficiency, and tPSA. The interaction of compound 4a and NAA50 has been further confirmed by co-crystal structure by Pfizer (pdb code: 6WFN).
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FBDD Case Studies
We have pioneered the use of off-rate screening (ORS) to kinetically sample hit-to-lead chemical space, combining our expertise in cheminformatics, compound library synthesis and use of surface plasmon resonance (SPR), to enable screening of unpurified reaction products. This has been applied to the rapid generation of lead compounds from fragment hits without purification of compound libraries or the use of protein structure (Murray, J. B. et al., J. Med. Chem. 2014).
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