Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 53, Issue 15, Pages 5639-5655Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm100383b
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Funding
- Cancer Research UK [C309/A8274, C107/A10433]
- Wellcome Trust
- Institute of Cancer Research
- Isle of Man Anti-Cancer Association
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Mutated BRAF serine/threonine kinase is implicated in several types of cancer, with particularly high frequency in melanoma and colorectal carcinoma. We recently reported on the development of BRAF inhibitors based on a tripartite A B C system featuring art imidazo[4,5]pyridin-2-one group hinge binder. Here we present the design, synthesis, and optimization of a new series of inhibitors with a different A B C system that has been modified by the introduction of a range of novel hinge binders (A ring). The optimization of the hinge binding moiety has enabled the development of compounds with low nanomolar potencies in both BRAF inhibition and cellular assays. These compounds display optimal pharmacokinetic properties that warrant further in vivo investigations.
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