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Issue 68, 2019
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Evaluation of linker length effects on a BET bromodomain probe

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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.

Graphical abstract: Evaluation of linker length effects on a BET bromodomain probe

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Publication details

The article was received on 02 Jul 2019, accepted on 01 Aug 2019 and first published on 01 Aug 2019


Article type: Communication
DOI: 10.1039/C9CC05054J
Chem. Commun., 2019,55, 10128-10131

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    Evaluation of linker length effects on a BET bromodomain probe

    R. Traquete, E. Henderson, S. Picaud, P. M. S. D. Cal, F. Sieglitz, T. Rodrigues, R. Oliveira, P. Filippakopoulos and G. J. L. Bernardes, Chem. Commun., 2019, 55, 10128
    DOI: 10.1039/C9CC05054J

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