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Fragment-Based Discovery of a Selective and Cell-Active Benzodiazepinone CBP/EP300 Bromodomain Inhibitor (CPI-637)
Alexander M Taylor1, Alexandre Côté1, Michael C Hewitt1
1Constellation Pharmaceuticals , 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
Abstract:
CBP and EP300 are highly homologous, bromodomain-containing transcription coactivators involved in numerous cellular pathways relevant to oncology. As part of our effort to explore the potential therapeutic implications of selectively targeting bromodomains, we set out to identify a CBP/EP300 bromodomain inhibitor that was potent both in vitro and in cellular target engagement assays and was selective over the other members of the bromodomain family. Reported here is a series of cell-potent and selective probes of the CBP/EP300 bromodomains, derived from the fragment screening hit 4-methyl-1,3,4,5-tetrahydro-2H-benzo[b][1,4]diazepin-2-one.
Insights
Researchers developed potent and selective inhibitors targeting CBP/EP300 bromodomains, crucial in cancer pathways. These compounds show promise for therapeutic development by engaging cellular targets effectively.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- CBP and EP300 are homologous bromodomain-containing transcription coactivators vital in cellular pathways, particularly in oncology.
- Targeting bromodomains presents a potential therapeutic strategy for various diseases.
Purpose of the Study:
- To identify a potent and selective inhibitor of CBP/EP300 bromodomains.
- To develop chemical probes for studying CBP/EP300 function and therapeutic targeting.
Main Methods:
- Fragment-based drug discovery approach.
- Synthesis and characterization of novel small molecules.
- In vitro biochemical assays to assess potency and selectivity.
- Cellular target engagement assays to evaluate in vivo activity.
Main Results:
- A series of potent and selective CBP/EP300 bromodomain inhibitors were identified.
- The developed compounds demonstrated cell potency and effective target engagement.
- Selectivity against other bromodomain-containing proteins was confirmed.
Conclusions:
- The identified compounds serve as valuable chemical probes for CBP/EP300.
- These inhibitors hold potential for further therapeutic development in oncology and other related fields.
