TY - JOUR
T1 - Rapid Elaboration of Fragments into Leads Applied to Bromodomain-3 Extra-Terminal Domain
AU - Adams, Luke A.
AU - Wilkinson-White, Lorna E.
AU - Gunzburg, Menachem J.
AU - Headey, Stephen J.
AU - Mohanty, Biswaranjan
AU - Scanlon, Martin J.
AU - Capuano, Ben
AU - Mackay, Joel P.
AU - Doak, Bradley C.
N1 - Funding Information:
The authors acknowledge funding from the NHMRC (APP1146355). L.A.A., B.C.D., and M.J.G. were supported by Monash Technology Research Platforms (MTRP). The authors acknowledge the use of the Bosch Molecular Biology Facility and the Sydney Analytical Magnetic Resonance Facility at the University of Sydney for providing access to SPR and NMR infrastructure, respectively. The authors thank Indu R. Chandrashekaran for insightful discussions around NMR data analysis.
Publisher Copyright:
© 2023 American Chemical Society.
PY - 2023/4/18
Y1 - 2023/4/18
N2 - The development of low-affinity fragment hits into higher-affinity leads is a major hurdle in fragment-based drug design. Here, we demonstrate the Rapid Elaboration of Fragments into Leads (REFiL) by 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. After a fragment screen against bromodomain-3 extra-terminal (BRD3-ET) domain, we applied the REFiL workflow, which allowed us to develop a series of ligands that bind to BRD3-ET. With REFiL, we were able to rapidly improve binding affinity > 30-fold. REFiL can be applied readily to a broad range of proteins without the need for a structure, allowing the efficient evolution of low-affinity fragments into higher-affinity leads and chemical probes.
AB - The development of low-affinity fragment hits into higher-affinity leads is a major hurdle in fragment-based drug design. Here, we demonstrate the Rapid Elaboration of Fragments into Leads (REFiL) by 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. After a fragment screen against bromodomain-3 extra-terminal (BRD3-ET) domain, we applied the REFiL workflow, which allowed us to develop a series of ligands that bind to BRD3-ET. With REFiL, we were able to rapidly improve binding affinity > 30-fold. REFiL can be applied readily to a broad range of proteins without the need for a structure, allowing the efficient evolution of low-affinity fragments into higher-affinity leads and chemical probes.
UR - http://www.scopus.com/inward/record.url?scp=85154029549&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.3c00137
DO - 10.1021/acs.jmedchem.3c00137
M3 - Article
C2 - 37071570
AN - SCOPUS:85154029549
SN - 0022-2623
VL - 66
SP - 5859
EP - 5872
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 8
ER -