CFT1946 Is an Orally Available Brain-Penetrant BRAFV600-Mutant Degrader That Overcomes BRAF Inhibitor Resistance

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Employing Digital Droplet PCR to Detect BRAF V600E Mutations in Formalin-fixed Paraffin-embedded Reference Standard Cell Lines
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Employing Digital Droplet PCR to Detect BRAF V600E Mutations in Formalin-fixed Paraffin-embedded Reference Standard Cell Lines

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Bridget T Kreger1, Yanke Liang1, Nicole M Reilly1

  • 1C4 Therapeutics, Inc., Watertown, Massachusetts.

Cancer Research
|October 28, 2025
PubMed

Insights

A new drug, CFT1946, effectively targets BRAFV600-mutant cancers, including melanoma and colorectal cancer. It overcomes resistance and side effects seen with current BRAF inhibitors (BRAFi), showing promise for improved cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Development

Background:

  • Approved BRAF inhibitors (BRAFi) show efficacy in BRAFV600-mutant cancers but face limitations.
  • Resistance mechanisms, poor brain penetration, and paradoxical MAPK activation limit BRAFi clinical benefit.
  • Novel therapeutic strategies are needed to overcome these BRAFi limitations.

Purpose of the Study:

  • To develop CFT1946, a novel cereblon-based bifunctional degrader targeting BRAFV600-mutant protein.
  • To overcome BRAFi resistance, improve brain penetration, and mitigate paradoxical MAPK activation.
  • To evaluate CFT1946's efficacy in preclinical models of BRAFV600-mutant cancers.

Main Methods:

  • Development of CFT1946, an orally bioavailable and brain-penetrant bifunctional degrader.
  • Preclinical testing in melanoma and colorectal cancer (CRC) models harboring BRAFV600 mutations.
  • Assessment of CFT1946's activity against RAF-dimer driven resistance and paradoxical MAPK activation.

Main Results:

  • CFT1946 demonstrated potent activity in BRAFV600-mutant melanoma and CRC models.
  • CFT1946 spared wild-type (WT) RAF signaling and mitigated paradoxical MAPK activation.
  • Efficacy was observed in an intracranial melanoma model and models of acquired BRAFi resistance.

Conclusions:

  • CFT1946 is a potent therapeutic agent for BRAFV600-mutant cancers.
  • CFT1946 overcomes key limitations of current BRAF inhibitors, including resistance and side effects.
  • CFT1946 represents a promising new treatment modality for targeted cancer therapy.

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