Inhibitors of BRAF dimers using an allosteric site.

Abstract

BRAF kinase, a critical effector of the ERK signaling pathway, is hyperactivated in many cancers. Oncogenic BRAFV600E signals as an active monomer in the absence of active RAS, however, in many tumors BRAF dimers mediate ERK signaling. FDA-approved RAF inhibitors poorly inhibit BRAF dimers, which leads to tumor resistance. We found that Ponatinib, an FDA-approved drug, is an effective inhibitor of BRAF monomers and dimers. Ponatinib binds the BRAF dimer and stabilizes a distinct αC-helix conformation through interaction with a previously unrevealed allosteric site. Using these structural insights, we developed PHI1, a BRAF inhibitor that fully uncovers the allosteric site. PHI1 exhibits discrete cellular selectivity for BRAF dimers, with enhanced inhibition of the second protomer when the first protomer is occupied, comprising a novel class of dimer selective inhibitors. This work shows that Ponatinib and BRAF dimer selective inhibitors will be useful in treating BRAF-dependent tumors.

• Authors: Xiomaris M Cotto-Rios, Bogos Agianian, Nadege Gitego, Emmanouil Zacharioudakis, Orsi Giricz, Yang Wu, Yiyu Zou, Amit Verma, Poulikos I Poulikakos, Evripidis Gavathiotis
• Journal: Nature communications (Nat Commun) Vol. 11 Issue 1 Pg. 4370 (09 01 2020) ISSN: 2041-1723 [Electronic] England
• PMID: 32873792 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Imidazoles
• Protein Kinase Inhibitors
• Protein Subunits
• Pyridazines
• Small Molecule Libraries
• ponatinib
• BRAF protein, human
• Proto-Oncogene Proteins B-raf

Topics

• Allosteric Site (drug effects)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Cell Line, Tumor
• Crystallography, X-Ray
• Drug Design
• Drug Screening Assays, Antitumor
• Humans
• Imidazoles (pharmacology, therapeutic use)
• MAP Kinase Signaling System (drug effects, genetics)
• Molecular Docking Simulation
• Mutation
• Neoplasms (drug therapy, genetics, pathology)
• Protein Kinase Inhibitors (chemistry, pharmacology, therapeutic use)
• Protein Multimerization (drug effects)
• Protein Subunits (antagonists & inhibitors, genetics, metabolism)
• Proto-Oncogene Proteins B-raf (antagonists & inhibitors, genetics, metabolism, ultrastructure)
• Pyridazines (pharmacology, therapeutic use)
• Small Molecule Libraries
• Structure-Activity Relationship