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Published on: May 15, 2019
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Biased multicomponent reactions to develop novel bromodomain inhibitors.
Michael R McKeown1, Daniel L Shaw, Harry Fu
1Department of Medical Oncology, Dana-Farber Cancer Institute , 450 Brookline Avenue, Boston, Massachusetts 02215, United States.
Journal of Medicinal Chemistry
|October 15, 2014
Summary
Researchers developed novel BET bromodomain inhibitors using fluorous synthesis. The lead compound, UMB-32, shows potent inhibition of BRD4 and TAF1, offering new epigenetic drug discovery avenues.
Area of Science:
- Medicinal Chemistry
- Epigenetics
- Chemical Biology
Background:
- Bromodomain and Extra-Terminal domain (BET) bromodomain inhibition is a key strategy in cancer therapy and gene regulation research.
- Existing BET inhibitors share structural similarities, necessitating the development of structurally distinct ligands for functional studies.
Purpose of the Study:
- To design and synthesize novel, structurally dissimilar BET bromodomain inhibitors.
- To explore new chemical scaffolds and synthetic methodologies for epigenetic drug discovery.
Main Methods:
- Utilized fluorous-tagged multicomponent reactions to create a focused chemical library.
- Employed iterative synthesis and biochemical assays for inhibitor optimization.
- Co-crystallized lead compound with BRD4 to determine structural interactions.
Main Results:
- Developed novel BET bromodomain inhibitors based on an imidazo[1,2-a]pyrazine scaffold.
- Identified lead compound 32 (UMB-32) with nanomolar binding affinity (Kd 550 nM) and cellular potency against BRD4.
- Demonstrated UMB-32's efficacy against TAF1, a previously underexplored target.
- Obtained a high-resolution crystal structure of UMB-32 bound to BRD4.
Conclusions:
- Fluorous and multicomponent synthesis are effective for developing novel epigenetic inhibitors.
- UMB-32 represents a promising lead compound for targeting BET bromodomains, including BRD4 and TAF1.
- The study provides new chemical probes for investigating bromodomain function and epigenetic regulation.
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