RAF inhibitors promote RAS-RAF interaction by allosterically disrupting RAF autoinhibition.

Autor:	Jin T; Institute for Research in Immunology and Cancer, Laboratory of Intracellular Signaling, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, QC, Canada, H3C 3J7., Lavoie H; Institute for Research in Immunology and Cancer, Laboratory of Intracellular Signaling, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, QC, Canada, H3C 3J7., Sahmi M; Institute for Research in Immunology and Cancer, Laboratory of Intracellular Signaling, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, QC, Canada, H3C 3J7., David M; Institute for Research in Immunology and Cancer, Laboratory of Intracellular Signaling, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, QC, Canada, H3C 3J7., Hilt C; Oncology Discovery, Bristol-Myers Squibb Research, Princeton, NJ, USA., Hammell A; Oncology Discovery, Bristol-Myers Squibb Research, Princeton, NJ, USA., Therrien M; Institute for Research in Immunology and Cancer, Laboratory of Intracellular Signaling, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, QC, Canada, H3C 3J7. marc.therrien@umontreal.ca.; Département de pathologie et biologie cellulaire, Université de Montréal, Outremont, QC, Canada, H2V 1E8. marc.therrien@umontreal.ca.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2017 Oct 31; Vol. 8 (1), pp. 1211. Date of Electronic Publication: 2017 Oct 31.
DOI:	10.1038/s41467-017-01274-0
Abstrakt:	First-generation RAF inhibitors paradoxically induce ERK signaling in normal and tumor cells exhibiting RAS activity. Compound-induced RAF dimerization through stabilization of the RAF ON/active state by inhibitors has emerged as a critical contributing factor. RAF inhibitors also enhance RAS-RAF association. Although this event is thought to play a key role in priming RAF activation, the underlying mechanism is not known. Here we report that RAF inhibitors induce the disruption of intramolecular interactions between the kinase domain and its N-terminal regulatory region independently of RAS activity. This provides a molecular basis to explain the induction of RAS-RAF association by RAF inhibitors, as well as the co-operativity observed between RAS activity and RAF kinase inhibitors in driving RAF activation. Profiling of second-generation RAF inhibitors confirmed their improved mode of action, but also revealed liabilities that allowed us to discern two properties of an ideal RAF inhibitor: high-binding affinity to all RAF paralogs and maintenance of the OFF/autoinhibited state of the enzyme.
Databáze:	MEDLINE
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