Related Experiment Video

Updated: Dec 10, 2025

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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Inhibitors of BRAF dimers using an allosteric site

Xiomaris M Cotto-Rios1,2, Bogos Agianian3,4, Nadege Gitego1,2

  • 1Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA.

Nature Communications
|September 3, 2020
PubMed

Insights

Ponatinib effectively inhibits BRAF monomers and dimers, offering a new strategy for cancer treatment. Researchers also developed PHI1, a novel dimer-selective BRAF inhibitor, to overcome drug resistance.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Drug Discovery

Background:

  • BRAF kinase is a key regulator of the ERK signaling pathway, frequently hyperactivated in various cancers.
  • While oncogenic BRAFV600E can signal as an active monomer, BRAF dimers are often responsible for ERK signaling in tumors.
  • Existing FDA-approved RAF inhibitors demonstrate limited efficacy against BRAF dimers, contributing to therapeutic resistance.

Purpose of the Study:

  • To investigate the inhibitory potential of Ponatinib against both BRAF monomers and dimers.
  • To elucidate the structural basis for Ponatinib's interaction with BRAF dimers.
  • To develop novel BRAF dimer-selective inhibitors for enhanced cancer therapy.

Main Methods:

  • Biochemical assays to assess the inhibitory activity of Ponatinib against BRAF monomers and dimers.
  • Structural biology techniques to determine the binding mode of Ponatinib to BRAF dimers.
  • Structure-based drug design to develop novel BRAF dimer inhibitors, exemplified by PHI1.

Main Results:

  • Ponatinib demonstrated significant inhibitory activity against both BRAF monomers and dimers.
  • Structural analysis revealed Ponatinib binds to a previously uncharacterized allosteric site on the BRAF dimer, stabilizing a unique αC-helix conformation.
  • PHI1, a novel inhibitor, was designed to target this allosteric site, exhibiting selective inhibition of BRAF dimers and enhanced activity on the second protomer.

Conclusions:

  • Ponatinib represents a promising therapeutic agent for BRAF-dependent cancers due to its dual inhibitory action on monomers and dimers.
  • The identification of a novel allosteric site on BRAF dimers opens new avenues for drug development.
  • Dimer-selective BRAF inhibitors, such as PHI1, offer a potential strategy to overcome resistance mechanisms in BRAF-driven tumors.

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