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.

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.

Novel BRD4 Degrader Discovery using DEL Technology

Advantages of using DEL Selection for Protein Degrader Discovery 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. More importantly, DEL selection is able to identify affinity binders for Protein Of Interest (POI) and E3 ligases, therefore it has advantages in creating stronger intellectual properties and exploring therapeutic benefit from novel E3 ligase(s) by their tissue distribution differences.

Identification of Transferase NAA50 Inhibitors by DEL Selection

Collaboration Project with Pfizer, ACS Med. Chem. Lett. 2020, 11, 1175−1184 Protein NAA50 and its Function The N-terminal-acetylation of a protein can affect its nuclear import and export and can also act as a degradation signal to control the protein’s cellular stability. The Nα-terminal acetyltransferase (Naa50) enzyme is a member of the Nα-terminal acetyltransferase NAT protein family. It coexists with Naa10 and Naa15 in the NatE complex and is responsible for the enzymatic function of the complex. Naa50 is also found to be essential for normal sister chromatid cohesion and chromosome condensation. Therefore, an inhibitor of the Naa50 enzyme might have therapeutic applications in oncology indications. The enzymatic catalysis and protein structure are shown below. 1617846309129650.png NAA50 Known Inhibitor and Objective of DEL Selection Compound 1 is designed by studies of the NAA50 biochemical mechanism which indicated formation of a ternary complex between the AcCoA cofactor, an appropriate protein substrate (tetra-peptide MLGP), and the enzyme. Although compound 1 is a potent Naa50 inhibitor, the molecule is not particularly efficient due to its large molecular weight (ligand efficiency (LE)10 = 0.13). In addition, its high molecular weight (MW = 1223) and high polarity (tPSA = 577 and cLogP = −4.1) likely prevents facile permeability across cell membranes and may thus compromise the use of the molecule as a robust in vitro tool compound.

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). By combining structural, thermodynamic and kinetic information from the wide range of ligand hits, we are able to design novel potent drug-like molecules. Our successes include generation of lead compounds that inhibit protein-protein interactions, ATPases and kinases, leading to clinical candidates for Mcl-1, Bcl-2, Hsp90 and Chk1. Published examples of our novel technologies and approach include use of our ORS technology in the identification of novel inhibitors of PDHK, and using our expertise in protein engineering, expression and crystallography to generate Chk1-derived surrogates of LRRK2.