1. Inhibition of RAF Isoforms and Active Dimers by LY3009120 Leads to Anti-tumor Activities in RAS or BRAF Mutant Cancers
- Author
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Bryan D. Smith, Xiwen Ma, Ilaria Conti, Daniel L. Flynn, Yue Webster, Subha Vogeti, Xiaoyi Zhang, Lisa Kays, Robert D. Van Horn, Phenil J. Patel, Youyan Zhang, Gregory P. Donoho, Shih-Hsun Chen, Sean Buchanan, Lawrence Chun, Lysiane Huber, Thomas J. Rutkoski, Tinggui Yin, Vipin Yadav, Denis J. McCann, Igor Mochalkin, Gregory D. Plowman, Henry James Robert, James J. Starling, Jennie L. Walgren, Sheng-Bin Peng, Wei-Ping Lu, Michael Kaufman, Xueqian Gong, and Scott C. Wise
- Subjects
Proto-Oncogene Proteins B-raf ,MAPK/ERK pathway ,Cancer Research ,endocrine system diseases ,MAP Kinase Signaling System ,Antineoplastic Agents ,Cell Line, Tumor ,Neoplasms ,medicine ,Humans ,Protein Isoforms ,Phosphorylation ,Kinase activity ,Vemurafenib ,Protein Kinase Inhibitors ,neoplasms ,Chemistry ,Phenylurea Compounds ,Dabrafenib ,Cell Biology ,Molecular biology ,digestive system diseases ,Proto-Oncogene Proteins c-raf ,enzymes and coenzymes (carbohydrates) ,Pyrimidines ,Oncology ,Mutation ,ras Proteins ,Cancer research ,Mitogen-Activated Protein Kinases ,ARAF ,Dimerization ,Signal Transduction ,medicine.drug - Abstract
SummaryLY3009120 is a pan-RAF and RAF dimer inhibitor that inhibits all RAF isoforms and occupies both protomers in RAF dimers. Biochemical and cellular analyses revealed that LY3009120 inhibits ARAF, BRAF, and CRAF isoforms with similar affinity, while vemurafenib or dabrafenib have little or modest CRAF activity compared to their BRAF activities. LY3009120 induces BRAF-CRAF dimerization but inhibits the phosphorylation of downstream MEK and ERK, suggesting that it effectively inhibits the kinase activity of BRAF-CRAF heterodimers. Further analyses demonstrated that LY3009120 also inhibits various forms of RAF dimers including BRAF or CRAF homodimers. Due to these unique properties, LY3009120 demonstrates minimal paradoxical activation, inhibits MEK1/2 phosphorylation, and exhibits anti-tumor activities across multiple models carrying KRAS, NRAS, or BRAF mutation.
- Published
- 2015