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Evaluation of linker length effects on a BET bromodomain probe.

Accepted version
Peer-reviewed

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Type

Article

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Authors

Traquete, Rui 
Henderson, Elizabeth 
Picaud, Sarah 
Cal, Pedro MSD 
Sieglitz, Florian 

Abstract

Fueled by the therapeutic potential of the epigenetic machinery, BET bromodomains have seen high interest as drug targets. Herein, we introduce different linkers to a BET bromodomain benzodiazepine ligand (I-BET762) to gauge its implications in the development of hybrid drugs, imaging probes and small molecule drug conjugates. Biophysical studies confirmed minimal disruption to binding of the BRD4 cavity by the synthesized entities, which includes imaging probes. Target engagement was confirmed in a cellular context, but poor membrane diffusion was found despite efficient localization in the nuclei after membrane disruption. Our study highlights challenges and opportunities for the successful design of benzodiazepine-derived drug-delivery systems.

Description

Keywords

Benzodiazepines, Cell Line, Tumor, Cell Nucleus, Drug Design, Fluoresceins, Fluorescent Dyes, Humans, Ligands, Molecular Structure, Nuclear Proteins, Protein Domains

Journal Title

Chemical Communications

Conference Name

Journal ISSN

1359-7345
1364-548X

Volume Title

55

Publisher

Royal Society of Chemistry

Rights

All rights reserved
Sponsorship
Royal Society (URF\R\180019)
We thank the Hovione Farmaciência (PhD studentship to R. T.) Royal Society (URF\R\180019 to G. J. L. B.), DFG (SI 2117/1-1 to F. S.), FCT Portugal (IF/00624/2015 to G. J. L. B., CEECIND/04518/2017 to P. M. S. D. C. and CEECIND/00887/2017 to T. R., and 02/SAICT/2017, Grant 28333 to T. R.) and the Medical Research Council (MRC grant MR/N010051/1 to P. F.) for funding.