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The discovery of potent and selective pyridopyrimidin-7-one based inhibitors of B-RafV600E kinase |
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| Authors: | Ren Li Ahrendt Kateri A Grina Jonas Laird Ellen R Buckmelter Alex J Hansen Joshua D Newhouse Brad Moreno David Wenglowsky Steve Dinkel Victoria Gloor Susan L Hastings Gregg Rana Sumeet Rasor Kevin Risom Tyler Sturgis Hillary L Voegtli Walter C Mathieu Simon |
| Institution: | Array BioPharma, Inc., 3200 Walnut Street, Boulder, CO 80301, United States. li.ren@arraybiopharma.com |
| Abstract: | Herein we describe the discovery of a novel series of ATP competitive B-Raf inhibitors via structure based drug design (SBDD). These pyridopyrimidin-7-one based inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. Optimization led to the identification of compound 17, a potent, selective and orally available agent with excellent pharmacokinetic properties and robust tumor growth inhibition in xenograft studies. |
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