A brain-penetrant RAF dimer antagonist for the noncanonical BRAF oncoprotein of pediatric low-grade astrocytomas

Neuro Oncol. 2017 Jun 1;19(6):774-785. doi: 10.1093/neuonc/now261.


Background: Activating mutations or structural rearrangements in BRAF are identified in roughly 75% of all pediatric low-grade astrocytomas (PLGAs). However, first-generation RAF inhibitors approved for adult melanoma have poor blood-brain penetrance and are only effective on tumors that express the canonical BRAFV600E oncoprotein, which functions as a monomer. These drugs (type I antagonists that target the "DFG-in" conformation of the kinase) fail to block signaling via KIAA1549:BRAF, a truncation/fusion BRAF oncoprotein which functions as a dimer and is found in the most common form of PLGA.

Methods: A panel of small molecule RAF inhibitors (including type II inhibitors, targeting the "DFG-out" conformation of the kinase) was screened for drugs showing efficacy on murine models of PLGA and on authentic human PLGA cells expressing KIAA1549:BRAF.

Results: We identify a type II RAF inhibitor that serves as an equipotent antagonist of BRAFV600E, KIAA1549:BRAF, and other noncanonical BRAF oncoproteins that function as dimers. This drug (MLN2480, also known as TAK-580) has good brain penetrance and is active on authentic human PLGA cells in brain organotypic cultures.

Conclusion: MLN2480 may be an effective therapeutic for BRAF mutant pediatric astrocytomas.

Keywords: MLN2480; RAF dimers; pediatric low-grade astrocytoma.

MeSH terms

  • Animals
  • Astrocytoma / drug therapy*
  • Astrocytoma / metabolism
  • Astrocytoma / pathology
  • Blood-Brain Barrier / drug effects
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology
  • Child
  • Heterocyclic Compounds, 3-Ring / chemistry
  • Heterocyclic Compounds, 3-Ring / pharmacology*
  • High-Throughput Screening Assays
  • Humans
  • Male
  • Mice
  • Oncogene Proteins, Fusion / antagonists & inhibitors*
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / metabolism
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Multimerization / drug effects*
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins B-raf / metabolism
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays
  • raf Kinases / antagonists & inhibitors*
  • raf Kinases / genetics
  • raf Kinases / metabolism


  • BRAF-KIAA1549 fusion protein, human
  • Heterocyclic Compounds, 3-Ring
  • MLN 2480
  • Oncogene Proteins, Fusion
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins B-raf
  • raf Kinases