Structural Basis of AZD9291 Selectivity for EGFR T790M

AZD9291
(Osimertinib) is highly effective in treating EGFR-mutated
non-small-cell lung cancers (NSCLCs) with T790M-mediated drug resistance.
Despite the remarkable success of AZD9291, its binding pose with EGFR
T790M remains unclear. Here, we report unbiased, atomic-level molecular
dynamics (MD) simulations in which spontaneous association of AZD9291
with EGFR kinases having WT and T790M mutant gatekeepers was observed.
Simulation-generated structural models suggest that the binding pose
of AZD9291 with T790M differs from its binding pose with the WT, and
that AZD9291 interacts extensively with the gatekeeper residue (Met
790) in T790M but not with Thr 790 in the WT, which explains why AZD9291
binds T790M with higher affinity. The MD simulation-generated models
were confirmed by experimentally determined EGFR/T790M complex crystal
structures. This work may facilitate the rational design of drugs
that can overcome resistance mutations to AZD9291, and more generally
it suggests the potential of using unbiased MD simulation to elucidate
small-molecule binding poses.