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Assessment of Bromodomain Target Engagement by a Series of BI2536 Analogues with Miniaturized BET‐BRET |
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| Authors: | Luke W Koblan Dr Dennis L Buckley Dr Christopher J Ott Dr Mark E Fitzgerald Dr Stuart W J Ember Dr Jin‐Yi Zhu Shuai Liu Justin M Roberts David Remillard Sarah Vittori Prof?Dr Wei Zhang Prof?Dr Ernst Schonbrunn Prof?Dr James E Bradner |
| Affiliation: | 1. Center for the Science of Therapeutics, Broad Institute, Cambridge, MA, USA;2. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA;3. Department of Medicine, Harvard Medical School, Boston, MA, USA;4. C4 Therapeutics, Cambridge, MA, USA;5. Drug Discovery Department, Moffitt Cancer Center, Tampa, FL, USA;6. Reaction Biology Corporation, Malvern, PA, USA;7. Department of Chemistry, University of Massachusetts-Boston, Boston, MA, USA;8. Novartis Institutes for Biomedical Research, Cambridge, MA, USA |
| 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 |