2. Academic Validation
  3. Demonstration of a genetic therapeutic index for tumors expressing oncogenic BRAF by the kinase inhibitor SB-590885

Demonstration of a genetic therapeutic index for tumors expressing oncogenic BRAF by the kinase inhibitor SB-590885

  • Cancer Res. 2006 Dec 1;66(23):11100-5. doi: 10.1158/0008-5472.CAN-06-2554.
Alastair J King 1,  Denis R Patrick,  Roberta S Batorsky,  Maureen L Ho,  Hieu T Do,  Shu Yun Zhang,  Rakesh Kumar,  David W Rusnak,  Andrew K Takle,  David M Wilson,  Erin Hugger,  Lifu Wang,  Florian Karreth,  Julie C Lougheed,  Jae Lee,  David Chau,  Thomas J Stout,  Earl W May,  Cynthia M Rominger,  Michael D Schaber,  Lusong Luo,  Ami S Lakdawala,  Jerry L Adams,  Rooja G Contractor,  Keiran S M Smalley,  Meenhard Herlyn,  Michael M Morrissey,  David A Tuveson,  Pearl S Huang
Affiliations

Affiliation

  • 1 Department of Oncology, MMPD CEDD, GlaxoSmithKline, Collegeville, Pennsylvania 19426, USA.
PMID: 17145850 DOI: 10.1158/0008-5472.CAN-06-2554
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-10966
    99.77%, Raf抑制剂
    Raf
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