Structural basis for the action of the drug trametinib at KSR-bound MEK

Abstract

The M APK/ E RK K inase MEK is a shared effector of the frequent cancer drivers KRAS and BRAF that has long been pursued as a drug target in oncology 1 , and more recently in immunotherapy 2 , 3 and aging 4 . However, many MEK inhibitors (MEKi) are limited due to on-target toxicities 5 – 7 and drug resistance 8 – 10 . Accordingly, a molecular understanding of the structure and function of MEK within physiological complexes could provide a template for the design of safer and more effective therapies. Here we report X-ray crystal structures of MEK bound to the scaffold KSR ( K inase S uppressor of R as) with various MEKi, including the clinical drug trametinib. The structures reveal an unexpected mode of binding in which trametinib directly engages KSR at the MEK interface. Through complexation, KSR remodels the prototypical MEKi allosteric pocket thereby impacting binding and kinetics, including drug residence time. Moreover, trametinib binds KSR-MEK but disrupts the related RAF-MEK complex through a mechanism that exploits evolutionarily conserved interface residues that distinguish these subcomplexes. Based on these insights we created trametiglue, which limits adaptive resistance to MEKi through enhanced interfacial binding. Together, our results reveal the plasticity of an interface pocket within MEK subcomplexes that has implications for the design of next generation drugs targeting the RAS pathway.

Kinase drug discovery 20 years after imatinib: progress and future directions

“…RAF and MEK interact with KSR1, an inactive pseudokinase that is structurally related to RAF. Interestingly, trametinib causes MEK to engage KSR1 more effectively, which may facilitate the ability of particular combinations of RAF and MEK inhibitors to target RAF–KSR–MEK complexes 60 . The first dual RAF–MEK inhibitor VS6766 (also known as CH5126766) has entered phase I clinical trials and has shown some efficacy in solid tumours and in multiple myeloma harbouring various RAS–RAF mutations 61 .…”

There’s more to death than life: Noncatalytic functions in kinase and pseudokinase signaling

“…An elegant recent study demonstrated that the MEK1 inhibitor Trametinib binds in a manner that enhances stability of a KSR-MEK1 complex ( Fig. 7 ; ( 107 )). Not only does this binding mode enhance residency of the inhibitor on MEK1, but the KSR-MEK1 complex is stabilized relative to the RAF-MEK1 complex, diminishing signaling flux through the pathway.…”

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Figure 7 Structure of the MEK1-KSR2-Trametinib complex. The overall structure of MEK1 ( tan ) binding to the KSR2 pseudokinase domain ( gray ; PDB 7jur; ( 107 )). An inset view below illustrates the intimate relationship between the MEK1 activation loop and Trametinib, which is stabilized by KSR2.

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Inhibition of RAF dimers: it takes two to tango

“…KSR1 contains a tyrosine within a conserved motif from the NtA region ( Figure 2 ), which could explain why KSR1 is able to transactivate BRAF unlike KSR2 [ 55 ]. A recent study has also shown the potential of targeting KSR1/2:MEK1/2 complexes, offering a potential therapeutic approach for targeting aberrant ERK1/2 signalling [ 56 , 57 ].…”