Virtual Lecture: New Approaches to Hit Generation Using Fragments and DNA-encoded Libraries

Lecture held on: November 28, 2024

Presenter

Prof. Mike Waring – Chemistry, School of Natural and Environmental Sciences, Newcastle University

In this lecture, Prof. Mike Waring of Newcastle University discussed his approach to DEL synthesis using micelle-mediated chemical reactions, which lead to much-improved efficiency and allow the synthesis of higher-fidelity DELs. Prof. Mike Waring has employed this technology to develop a range of library-forming reactions, including Suzuki, amide, Buchwald, Heck, and Sonogashira couplings, as well as reductive aminations and hydrogenation.

Prof. Waring has employed this chemistry in synthesizing screening libraries and poised DELs for fragment expansion, termed NUDELs. NUDELs are poised DELs built combinatorially from diverse building blocks and contain a reactive handle, allowing selected fragments to be incorporated. This allows an active fragment to be developed into a potent ligand in a single step.

Alternatively, they could be viewed as a way of rapidly generating focused DELs for selected targets. This approach has been demonstrated by developing a potent and highly ligand-efficient lead for BRD4 from a weak fragment whose affinity arises from synergistic protein-ligand interactions that other means could not have discovered.