Trends in Hit-to-Lead Optimization Following DNA-Encoded Library Screens

Abstract

DNA-encoded library (DEL) screens have emerged as a powerful hit-finding tool for a number of biological targets. In this Innovations article, we review published hit-to-lead optimization studies following DEL screens. Trends in molecular property changes from hit to lead are identified, and specific optimization tactics are exemplified in case studies. Across the studies, physicochemical property and structural changes post-DEL screening are similar to those which occur during hit-to-lead optimization following high throughputscreens (HTS). However, unique aspects of DELthe combinatorial synthetic methods which enable DEL synthesis and the linker effects at the DNA attachment pointimpact the strategies and outcomes of hit-to-lead optimizations.

Target-Based Evaluation of “Drug-Like” Properties and Ligand Efficiencies

“…Achieving suitable pharmacokinetic properties was a major challenge, yet notably, most of the privileged structure pharmacophoric elements in 1 were ultimately retained (Figure a), with the exception of the benzo fusion. In general, retention of pharmacophoric features in hit optimization is often seen. , Extracting higher potency with little change to MW, resulting in increased LE, was also consistently seen in a set of 15 hit-to-lead optimizations derived from DNA-encoded libraries, where the average hit MW was 533 …”

“…31,66 Extracting higher potency with little change to MW, resulting in increased LE, was also consistently seen in a set of 15 hit-to-lead optimizations derived from DNA-encoded libraries, where the average hit MW was 533. 69 The first two CGRP antagonist clinical candidates, 2 and 3, had to be abandoned because of hepatotoxicity in the clinic, and based on the published patents, it took 8 years to move from the first candidate 2 to the successful drug 4. The time frame reflects the challenge of multiparameter ADMET optimization for this difficult target, the wealth of options for modification that are presented by the hit structure 1, and not least, the considerable commitment needed from the project team.…”

Chemical Evolution of Natural Product Structure

“… 9 A combinatorial approach utilizing DNA encoded libraries (DEL) has emerged as a method for the generation of relatively large libraries with chemical diversity. 10 While DOS and DEL can generate expansive libraries that can quickly explore diverse chemical space, more recently in tandem, 11 and have provided biologically valuable compounds, 12 , 13 much of the space explored may not necessarily be biologically relevant.…”

On the design of lead-like DNA-encoded chemical libraries

“…Ideally, they should be focused on lead-like chemical space (low molecular weight and balanced lipophilicity) 8,9 such that hits are optimisable, accepting that the ability to screen large number of compounds increases the chances of finding hits for larger, more complex compounds. 10 The chemical space populated by a DEL is entirely governed by the chemistry that is used in its construction: the reactions that are used to synthesise the library and the building blocks that are selected for each step. The need to carry-out DNA compatible chemistry 11 limits, to a degree, the choice of reactions that are employed, although the range of reactions that can be used is increasing.…”