AI Article Synopsis
- Researchers developed new ATP competitive B-Raf inhibitors using structure-based methods, specifically focusing on 3-N-methylquinazoline-4(3H)-one compounds.
- These inhibitors showed strong efficacy in cancer cells and high selectivity for B-Raf, leading to the discovery of compound 16, which is potent, selective, and can be taken orally.
- The study also revealed that altering an aryl amide to an aryl sulfonamide can transform a multikinase inhibitor into a selective B-Raf inhibitor, offering valuable insights for future kinases drug development.
Article Abstract
Herein we describe the design of a novel series of ATP competitive B-Raf inhibitors via structure-based methods. These 3-N-methylquinazoline-4(3H)-one based inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. Optimization led to the identification of compound 16, a potent, selective and orally available agent with excellent pharmacokinetic properties and robust tumor growth inhibition in xenograft studies. Our work also demonstrates that by replacing an aryl amide with an aryl sulfonamide, a multikinase inhibitor such as AZ-628, can be converted to a selective B-Raf inhibitor, a finding that should have broad application in kinase drug discovery.
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| http://dx.doi.org/10.1016/j.bmcl.2014.03.007 | DOI Listing |
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