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Updated: Nov 12, 2025

Light-mediated Reversible Modulation of the Mitogen-activated Protein Kinase Pathway during Cell Differentiation and Xenopus Embryonic Development
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Selective CRAF Inhibition Elicits Transactivation

Charles W Morgan1, Ian L Dale2, Andrew P Thomas3

  • 1Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom.

Journal of the American Chemical Society
|March 22, 2021
PubMed

Insights

Targeting CRAF (a RAF kinase) selectively may paradoxically activate RAF signaling, contrary to hypotheses. This study used bio-orthogonal ligand tethering (BOLT) to investigate CRAF inhibition, revealing implications for cancer drug discovery.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Discovering isoform-specific drugs is difficult, with unknown consequences of isoform regulation.
  • RAF kinases (BRAF, CRAF) are key in MAP kinase signaling and often mutated in cancer.
  • Current RAF inhibitors can cause paradoxical activation via CRAF, leading to resistance.

Purpose of the Study:

  • To investigate the effects of selective CRAF inhibition.
  • To explore if CRAF-selective inhibition bypasses paradoxical activation.
  • To demonstrate the utility of bio-orthogonal ligand tethering (BOLT) for target validation.

Main Methods:

  • Utilized bio-orthogonal ligand tethering (BOLT) to selectively target inhibitors to CRAF.
  • Investigated the downstream signaling consequences of selective CRAF inhibition.

Main Results:

  • Selective CRAF inhibition was found to promote paradoxical activation of RAF signaling.
  • This finding challenges the hypothesis that CRAF-selective inhibition would bypass paradoxical activation.
  • Demonstrated BOLT as a method for early-stage target triage in drug discovery.

Conclusions:

  • Selective CRAF inhibition can lead to paradoxical activation, similar to broader RAF inhibition.
  • BOLT is a valuable tool for assessing the consequences of targeting specific protein isoforms early in drug discovery.
  • Understanding CRAF's role is crucial for developing effective cancer therapies and overcoming drug resistance.

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