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Boulder City, CO, United States

Wenglowsky S.,ArrayBioPharma | Ahrendt K.A.,ArrayBioPharma | Buckmelter A.J.,ArrayBioPharma | Feng B.,Genentech | And 16 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2011

Structure-activity relationships around a novel series of B-Raf V600E inhibitors are reported. The enzymatic and cellular potencies of inhibitors derived from two related hinge-binding groups were compared and3-methoxypyrazolopyridine proved to be superior. The 3-alkoxy group of lead B-Raf V600E inhibitor 1 was extended and minimally affected potency. The propyl sulfonamide tail of compound 1, which occupies the small lipophilic pocket formed by an outward shift of the αC-helix, was expanded to a series of arylsulfonamides. X-ray crystallography revealed that this lipophilic pocket unexpectedly enlarges to accommodate the bulkier aryl group. © 2011 Elsevier Ltd. All rights reserved.

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