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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
The Discovery of Exarafenib (KIN-2787): Overcoming the Challenges of Pan-RAF Kinase Inhibition
Young K Chen1, Toufike Kanouni1, Lee D Arnold1
1Kinnate Biopharma, 12830 El Camino Real, Suite 150, San Diego, California 92130, United States.
Abstract:
RAF, a core signaling component of the MAPK kinase cascade, is often mutated in various cancers, including melanoma, lung, and colorectal cancers. The approved inhibitors were focused on targeting the BRAFV600E mutation that results in constitutive activation of kinase signaling through the monomeric protein (Class I). However, these inhibitors also paradoxically activate kinase signaling of RAF dimers, resulting in increased MAPK signaling in normal tissues. Recently, significant attention has turned to targeting RAF alterations that activate dimeric signaling (class II and III BRAF and NRAS). However, the discovery of a potent and selective inhibitor with biopharmaceutical properties suitable to sustain robust target inhibition in the clinical setting has proven challenging. Herein, we report the discovery of exarafenib (15), a highly potent and selective inhibitor that intercepts the RAF protein in the dimer compatible αC-helix-IN conformation and demonstrates anti-tumor efficacy in preclinical models with BRAF class I, II, and III and NRAS alterations.
Insights
A new drug, exarafenib, effectively inhibits RAF dimers implicated in various cancers. This potent and selective inhibitor shows promise for treating tumors with BRAF and NRAS alterations, overcoming limitations of current therapies.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- RAF proteins are key regulators of the MAPK signaling pathway, frequently altered in cancers like melanoma, lung, and colorectal cancers.
- Existing BRAF inhibitors primarily target Class I mutations (e.g., BRAFV600E) but can paradoxically activate RAF dimers, leading to increased MAPK signaling.
- Targeting RAF dimer-activating alterations (Class II/III BRAF, NRAS) is a critical unmet need, but developing suitable inhibitors has been challenging.
Purpose of the Study:
- To discover and characterize a novel, potent, and selective inhibitor targeting RAF dimer-compatible conformations.
- To evaluate the anti-tumor efficacy of the novel inhibitor in preclinical models harboring various RAF and NRAS alterations.
Main Methods:
- Discovery of exarafenib (compound 15) through targeted inhibitor development.
- Biochemical assays to assess potency and selectivity against RAF dimers.
- In vivo preclinical studies using tumor models with BRAF Class I, II, III, and NRAS alterations.
Main Results:
- Exarafenib potently and selectively inhibits RAF proteins in a dimer-compatible conformation.
- The inhibitor demonstrates significant anti-tumor efficacy across preclinical models with diverse BRAF and NRAS alterations.
- Exarafenib overcomes the paradoxical activation seen with existing Class I BRAF inhibitors.
Conclusions:
- Exarafenib represents a promising therapeutic candidate for a broad spectrum of RAF-driven and NRAS-mutated cancers.
- This novel inhibitor offers a potential strategy to overcome resistance and limitations associated with current RAF-targeted therapies.
- The discovery highlights the therapeutic potential of targeting RAF dimer conformations for cancer treatment.
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