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Rapid Elaboration of Fragments into Leads Applied to Bromodomain-3 Extra Terminal Domain

submitted on 24.03.2020, 23:09 and posted on 25.03.2020, 12:38 by Luke Adams, Lorna E. Wilkinson-White, Menachem J. Gunzburg, Stephen J. Headey, Martin J. Scanlon, Ben Capuano, Joel P. Mackay, Bradley Doak
The development of low-affinity fragment hits into higher affinity leads is a major hurdle in fragment-based drug design. Here we demonstrate an approach for the Rapid Elaboration of Fragments into Leads (REFiL) applying an integrated workflow that provides a systematic approach to generate higher-affinity binders without the need for structural information. The workflow involves the selection of commercial analogues of fragment hits to generate preliminary structure-activity relationships. This is followed by parallel microscale chemistry using chemoinformatically designed reagent libraries to rapidly explore chemical diversity. Upon completion of a fragment screen against Bromodomain-3 extra terminal (BRD3-ET) domain we applied the REFiL workflow, which allowed us to develop a series of tetrahydrocarbazole ligands that bind to the peptide binding site of BRD3-ET. With REFiL we were able to rapidly improve binding affinity >30-fold. The REFiL workflow can be applied readily to a broad range of protein targets without the need of a structure, allowing the efficient evolution of low-affinity fragments into higher affinity leads and chemical probes.


NHMRC (APP1146355)


Email Address of Submitting Author


Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University



ORCID For Submitting Author


Declaration of Conflict of Interest

The authors declare no competing financial interest.