2fb8: Difference between revisions

Line 4:

==Overview==

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.

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.

==Disease==

Line 17:

[[Category: Non-specific serine/threonine protein kinase]]

[[Category: Single protein]]

[[Category: Chau, D.C.]]

[[Category: Chau, D C.]]

[[Category: Lee, J.]]

[[Category: Lougheed, J.C.]]

[[Category: Lougheed, J C.]]

[[Category: Stout, T.J.]]

[[Category: Stout, T J.]]

[[Category: 215]]

[[Category: kinase domain]]

''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on ~~Fri~~ Feb 15 17:24:57 2008''

''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:19:36 2008''

Navigation menu

Page actions

Page actions

Personal tools

Navigation

Search

Tools

@@ Line 4: / Line 4: @@
 ==Overview==
-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.
+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.
 ==Disease==
@@ Line 17: / Line 17: @@
 [[Category: Non-specific serine/threonine protein kinase]]
 [[Category: Single protein]]
-[[Category: Chau, D.C.]]
+[[Category: Chau, D C.]]
 [[Category: Lee, J.]]
-[[Category: Lougheed, J.C.]]
+[[Category: Lougheed, J C.]]
-[[Category: Stout, T.J.]]
+[[Category: Stout, T J.]]
 [[Category: 215]]
 [[Category: kinase domain]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri Feb 15 17:24:57 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:19:36 2008''