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Updated: Apr 4, 2026

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
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Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

Published on: July 17, 2019

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

Sheng-Bin Peng1, James R Henry1, Michael D Kaufman2

  • 1Eli Lilly and Company, Indianapolis, IN 46285, USA.

Cancer Cell
|September 8, 2015
PubMed

Insights

LY3009120 is a novel pan-RAF inhibitor that blocks all RAF isoforms and their dimers. This drug shows anti-tumor activity in models with KRAS, NRAS, or BRAF mutations, with minimal paradoxical activation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • RAF kinases (ARAF, BRAF, CRAF) are key regulators of the MAPK pathway.
  • Aberrant RAF signaling drives various cancers, making RAF inhibitors a therapeutic target.
  • Existing BRAF inhibitors often have limited CRAF activity and can cause paradoxical pathway activation.

Purpose of the Study:

  • To characterize LY3009120, a novel pan-RAF and RAF dimer inhibitor.
  • To evaluate its inhibitory profile against RAF isoforms and dimers.
  • To assess its efficacy and safety in preclinical cancer models.

Main Methods:

  • Biochemical and cellular assays to determine RAF isoform and dimer inhibition.
  • Analysis of downstream MEK and ERK phosphorylation.
  • Evaluation of anti-tumor activity in various cancer models with specific mutations.

Main Results:

  • LY3009120 inhibits ARAF, BRAF, and CRAF isoforms with similar high affinity.
  • It effectively inhibits BRAF-CRAF heterodimers and other RAF homodimers.
  • The drug demonstrated minimal paradoxical activation and inhibited MEK1/2 phosphorylation.
  • LY3009120 exhibited anti-tumor activity in KRAS, NRAS, or BRAF mutant models.

Conclusions:

  • LY3009120 is a potent pan-RAF inhibitor with unique RAF dimer inhibitory properties.
  • Its broad RAF inhibition and lack of significant paradoxical activation contribute to its anti-tumor efficacy.
  • LY3009120 represents a promising therapeutic candidate for cancers with RAS or RAF mutations.

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