Related Experiment Video

Updated: Apr 28, 2026

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
07:49

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

Published on: July 17, 2019

5.7K

Discovery of Dabrafenib: A Selective Inhibitor of Raf Kinases with Antitumor Activity against B-Raf-Driven Tumors

Tara R Rheault1, John C Stellwagen1, George M Adjabeng1

  • 1Oncology R&D Medicinal Chemistry, GlaxoSmithKline , Research Triangle Park , North Carolina 27709, United States.

ACS Medicinal Chemistry Letters
|June 6, 2014
PubMed

Insights

A new drug, GSK2118436, effectively targets the mutated B-Raf enzyme common in melanomas. This potent Raf kinase inhibitor shows significant antitumor activity in preclinical models and early clinical trials for B-Raf mutant melanoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Aberrant mitogen-activated protein kinase (MAPK) pathway signaling, driven by mutations like B-Raf(V600E), is implicated in various human cancers, notably melanoma.
  • The B-Raf(V600E) mutation leads to constitutive pathway activation, promoting tumor cell proliferation and survival.

Purpose of the Study:

  • To discover and biologically evaluate GSK2118436, a novel selective inhibitor targeting Raf kinases.
  • To assess the in vitro and in vivo efficacy of GSK2118436 in models of B-Raf-driven cancers.

Main Methods:

  • In vitro assays were performed to determine the activity of GSK2118436 against oncogenic B-Raf mutated melanoma and colorectal carcinoma cells.
  • In vivo studies evaluated the antitumor and pharmacodynamic effects of GSK2118436 in mouse models harboring B-Raf(V600E) human melanoma.

Main Results:

  • GSK2118436 demonstrated potent in vitro activity against B-Raf(V600E)-driven cancer cells.
  • Robust in vivo antitumor and pharmacodynamic effects were observed in preclinical models.
  • Early clinical data indicate significant therapeutic activity in patients with B-Raf mutant melanoma.

Conclusions:

  • GSK2118436 is a potent and selective Raf kinase inhibitor with promising preclinical and early clinical activity.
  • GSK2118436 represents a potential targeted therapy for B-Raf mutant melanoma and other B-Raf-driven malignancies.
Keywords:
B-RafGSK2118436MAP kinasedabrafenibmelanoma

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