Demonstration of a Genetic Therapeutic Index for Tumors Expressing Oncogenic BRAF by the Kinase Inhibitor SB-590885

@article{citeulike:1587605, abstract = {Oncogenic BRAF alleles are both necessary and sufficient for cellular transformation, suggesting that chemical inhibition of the activated mutant protein kinase may reverse the tumor phenotype. Here, we report the characterization of SB-590885, a novel triarylimidazole that selectively inhibits Raf kinases with more potency towards B-Raf than c-Raf. Crystallographic analysis revealed that SB-590885 stabilizes the oncogenic B-Raf kinase domain in an active configuration, which is distinct from the previously reported mechanism of action of the multi-kinase inhibitor, BAY43-9006. Malignant cells expressing oncogenic B-Raf show selective inhibition of mitogen-activated protein kinase activation, proliferation, transformation, and tumorigenicity when exposed to SB-590885, whereas other cancer cell lines and normal cells display variable sensitivities or resistance to similar treatment. These studies support the validation of oncogenic B-Raf as a target for cancer therapy and provide the first evidence of a correlation between the expression of oncogenic BRAF alleles and a positive response to a selective B-Raf inhibitor. (Cancer Res 2006; 66(23): 11100-5) 10.1158/0008-5472.CAN-06-2554}, author = {King, Alastair J. and Patrick, Denis R. and Batorsky, Roberta S. and Ho, Maureen L. and Do, Hieu T. and Zhang, Shu Y. and Kumar, Rakesh and Rusnak, David W. and Takle, Andrew K. and Wilson, David M. and Hugger, Erin and Wang, Lifu and Karreth, Florian and Lougheed, Julie C. and Lee, Jae and Chau, David and Stout, Thomas J. and May, Earl W. and Rominger, Cynthia M. and Schaber, Michael D. and Luo, Lusong and Lakdawala, Ami S. and Adams, Jerry L. and Contractor, Rooja G. and Smalley, Keiran S. and Herlyn, Meenhard and Morrissey, Michael M. and Tuveson, David A. and Huang, Pearl S. }, citeulike-article-id = {1587605}, doi = {10.1158/0008-5472.CAN-06-2554}, journal = {Cancer Res}, keywords = {braf, gsk, sb-590885, structure}, month = {December}, number = {23}, pages = {11100--11105}, posted-at = {2007-08-24 12:02:35}, priority = {0}, title = {Demonstration of a Genetic Therapeutic Index for Tumors Expressing Oncogenic BRAF by the Kinase Inhibitor SB-590885}, url = {http://dx.doi.org/10.1158/0008-5472.CAN-06-2554}, volume = {66}, year = {2006} }

TY - JOUR ID - citeulike:1587605 L3 - citeulike-article-id:1587605 TI - Demonstration of a Genetic Therapeutic Index for Tumors Expressing Oncogenic BRAF by the Kinase Inhibitor SB-590885 JF - Cancer Res VL - 66 IS - 23 SP - 11100 EP - 11105 N2 - Oncogenic BRAF alleles are both necessary and sufficient for cellular transformation, suggesting that chemical inhibition of the activated mutant protein kinase may reverse the tumor phenotype. Here, we report the characterization of SB-590885, a novel triarylimidazole that selectively inhibits Raf kinases with more potency towards B-Raf than c-Raf. Crystallographic analysis revealed that SB-590885 stabilizes the oncogenic B-Raf kinase domain in an active configuration, which is distinct from the previously reported mechanism of action of the multi-kinase inhibitor, BAY43-9006. Malignant cells expressing oncogenic B-Raf show selective inhibition of mitogen-activated protein kinase activation, proliferation, transformation, and tumorigenicity when exposed to SB-590885, whereas other cancer cell lines and normal cells display variable sensitivities or resistance to similar treatment. These studies support the validation of oncogenic B-Raf as a target for cancer therapy and provide the first evidence of a correlation between the expression of oncogenic BRAF alleles and a positive response to a selective B-Raf inhibitor. (Cancer Res 2006; 66(23): 11100-5) 10.1158/0008-5472.CAN-06-2554 KW - braf KW - gsk KW - sb-590885 KW - structure AU - King, Alastair AU - Patrick, Denis AU - Batorsky, Roberta AU - Ho, Maureen AU - Do, Hieu AU - Zhang, Shu AU - Kumar, Rakesh AU - Rusnak, David AU - Takle, Andrew AU - Wilson, David AU - Hugger, Erin AU - Wang, Lifu AU - Karreth, Florian AU - Lougheed, Julie AU - Lee, Jae AU - Chau, David AU - Stout, Thomas AU - May, Earl AU - Rominger, Cynthia AU - Schaber, Michael AU - Luo, Lusong AU - Lakdawala, Ami AU - Adams, Jerry AU - Contractor, Rooja AU - Smalley, Keiran AU - Herlyn, Meenhard AU - Morrissey, Michael AU - Tuveson, David AU - Huang, Pearl PY - 2006/12/01/ UR - http://dx.doi.org/10.1158/0008-5472.CAN-06-2554 ER -