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

Ting Jin, Hugo Lavoie, Malha Sahmi, Maud David, Christine Hilt, Amy Hammell and Marc Therrien ()
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Ting Jin: Université de Montréal
Hugo Lavoie: Université de Montréal
Malha Sahmi: Université de Montréal
Maud David: Université de Montréal
Christine Hilt: Bristol-Myers Squibb Research
Amy Hammell: Bristol-Myers Squibb Research
Marc Therrien: Université de Montréal

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/s41467-017-01274-0

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