Inhibitors of BRAF dimers using an allosteric site

Xiomaris M. Cotto-Rios, Bogos Agianian (), Nadege Gitego, Emmanouil Zacharioudakis, Orsi Giricz, Yang Wu, Yiyu Zou, Amit Verma, Poulikos I. Poulikakos and Evripidis Gavathiotis ()
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Xiomaris M. Cotto-Rios: Albert Einstein College of Medicine
Bogos Agianian: Albert Einstein College of Medicine
Nadege Gitego: Albert Einstein College of Medicine
Emmanouil Zacharioudakis: Albert Einstein College of Medicine
Orsi Giricz: Albert Einstein College of Medicine, Montefiore Medical Center
Yang Wu: Albert Einstein College of Medicine
Yiyu Zou: Albert Einstein College of Medicine
Amit Verma: Albert Einstein College of Medicine, Montefiore Medical Center
Poulikos I. Poulikakos: Icahn School of Medicine at Mount Sinai
Evripidis Gavathiotis: Albert Einstein College of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18123-2

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