TY - JOUR
T1 - Inhibitors of BRAF dimers using an allosteric site
AU - Cotto-Rios, Xiomaris M.
AU - Agianian, Bogos
AU - Gitego, Nadege
AU - Zacharioudakis, Emmanouil
AU - Giricz, Orsi
AU - Wu, Yang
AU - Zou, Yiyu
AU - Verma, Amit
AU - Poulikakos, Poulikos I.
AU - Gavathiotis, Evripidis
N1 - Funding Information:
We thank Jeffrey B. Bonanno, Tyler L. Grove, and staff of the X-ray Crystallography core facility of Albert Einstein College of Medicine for their support. Studies were supported by grants from the Melanoma Research Alliance and the Irma Hirschl Trust. Additional support from NIH grants R01CA238229, R01CA204314, and P30CA013330. X.C.R. was supported by an American Cancer Society fellowship (PF-16-097-CDD) and a T32 Training Grant T32 AG 23475. This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-020-18123-2
DO - 10.1038/s41467-020-18123-2
M3 - Article
C2 - 32873792
AN - SCOPUS:85090056480
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4370
ER -
