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.