2. Academic Validation
  3. Inhibition of RAF Isoforms and Active Dimers by LY3009120 Leads to Anti-tumor Activities in RAS or BRAF Mutant Cancers

Inhibition of RAF Isoforms and Active Dimers by LY3009120 Leads to Anti-tumor Activities in RAS or BRAF Mutant Cancers

  • Cancer Cell. 2015 Sep 14;28(3):384-98. doi: 10.1016/j.ccell.2015.08.002.
Sheng-Bin Peng 1,  James R Henry 2,  Michael D Kaufman 3,  Wei-Ping Lu 3,  Bryan D Smith 3,  Subha Vogeti 3,  Thomas J Rutkoski 3,  Scott Wise 3,  Lawrence Chun 4,  Youyan Zhang 2,  Robert D Van Horn 2,  Tinggui Yin 2,  Xiaoyi Zhang 2,  Vipin Yadav 2,  Shih-Hsun Chen 2,  Xueqian Gong 2,  Xiwen Ma 2,  Yue Webster 2,  Sean Buchanan 2,  Igor Mochalkin 2,  Lysiane Huber 2,  Lisa Kays 2,  Gregory P Donoho 2,  Jennie Walgren 2,  Denis McCann 2,  Phenil Patel 2,  Ilaria Conti 2,  Gregory D Plowman 2,  James J Starling 2,  Daniel L Flynn 3
Affiliations

Affiliations

  • 1 Eli Lilly and Company, Indianapolis, IN 46285, USA. Electronic address: [email protected].
  • 2 Eli Lilly and Company, Indianapolis, IN 46285, USA.
  • 3 Deciphera Pharmaceuticals, LLC, Lawrence, KS 66044, USA.
  • 4 Emerald Biostructures, Bainbridge Island, WA 98110, USA.
PMID: 26343583 DOI: 10.1016/j.ccell.2015.08.002
Abstract

LY3009120 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.

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