Download MendeleyDiscovery and Optimization of a Novel Series of Potent Mutant B-Raf V600E Selective Kinase Inhibitors.
Vasbinder, M.M., Aquila, B., Augustin, M., Chen, H., Cheung, T., Cook, D., Drew, L., Fauber, B.P., Glossop, S., Grondine, M., Hennessy, E.J., Johannes, J., Lee, S., Lyne, P.D., Mortl, M., Omer, C., Palakurthi, S., Pontz, T., Read, J., Sha, L., Shen, M., Steinbacher, S., Wang, H., Wu, A., Ye, M.(2013) J Med Chem 56: 1996
- PubMed: 23398453
- DOI: https://doi.org/10.1021/jm301658d
- Primary Citation of Related Structures:
4BB4, 4H58 - PubMed Abstract:
B-Raf represents an attractive target for anticancer therapy and the development of small molecule B-Raf inhibitors has delivered new therapies for metastatic melanoma patients. We have discovered a novel class of small molecules that inhibit mutant B-Raf(V600E) kinase activity both in vitro and in vivo. Investigations into the structure-activity relationships of the series are presented along with efforts to improve upon the cellular potency, solubility, and pharmacokinetic profile. Compounds selectively inhibited B-Raf(V600E) in vitro and showed preferential antiproliferative activity in mutant B-Raf(V600E) cell lines and exhibited selectivity in a kinase panel against other kinases. Examples from this series inhibit growth of a B-Raf(V600E) A375 xenograft in vivo at a well-tolerated dose. In addition, aminoquinazolines described herein were shown to display pERK elevation in nonmutant B-Raf cell lines in vitro.
Organizational Affiliation:
Oncology iMED, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States. melissa.vasbinder@astrazeneca.com
