2. Academic Validation
  3. Assessment of Bromodomain Target Engagement by a Series of BI2536 Analogues with Miniaturized BET-BRET

Assessment of Bromodomain Target Engagement by a Series of BI2536 Analogues with Miniaturized BET-BRET

  • ChemMedChem. 2016 Dec 6;11(23):2575-2581. doi: 10.1002/cmdc.201600502.
Luke W Koblan 1,  Dennis L Buckley 2 3,  Christopher J Ott 2 3 1,  Mark E Fitzgerald 1 4,  Stuart W J Ember 5 6,  Jin-Yi Zhu 5,  Shuai Liu 7,  Justin M Roberts 2,  David Remillard 2,  Sarah Vittori 2 1,  Wei Zhang 7,  Ernst Schonbrunn 5,  James E Bradner 2 3 1 8
Affiliations

Affiliations

  • 1 Center for the Science of Therapeutics, Broad Institute, Cambridge, MA, 02142, USA.
  • 2 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
  • 3 Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA.
  • 4 C4 Therapeutics, Cambridge, MA, 02142, USA.
  • 5 Drug Discovery Department, Moffitt Cancer Center, Tampa, FL, 33612, USA.
  • 6 Reaction Biology Corporation, Malvern, PA, 19355, USA.
  • 7 Department of Chemistry, University of Massachusetts-Boston, Boston, MA, 02125, USA.
  • 8 Novartis Institutes for Biomedical Research, Cambridge, MA, 02139, USA.
PMID: 27862999 DOI: 10.1002/cmdc.201600502
Abstract

Evaluating the engagement of a small molecule ligand with a protein target in cells provides useful information for chemical probe optimization and pharmaceutical development. While several techniques exist that can be performed in a low-throughput manner, systematic evaluation of large compound libraries remains a challenge. In-cell engagement measurements are especially useful when evaluating compound classes suspected to target multiple cellular factors. In this study we used a bioluminescent resonant energy transfer assay to assess bromodomain engagement by a compound series containing bromodomain- and kinase-biasing polypharmacophores based on the known dual BRD4 bromodomain/PLK1 kinase inhibitor BI2536. With this assay, we discovered several novel agents with bromodomain-selective specificity profiles and cellular activity. Thus, this platform aids in distinguishing molecules whose cellular activity is difficult to assess due to polypharmacologic effects.

Keywords

bromodomain inhibition; drug design; epigenetics; fluorescence; in-cell target engagement assays; luminescence.

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