mTOR Variants Activation Discovers PI3K-like Cryptic Pocket, Expanding Allosteric, Mutant-Selective Inhibitor Designs

mTOR plays a crucial role in PI3K/AKT/mTOR
signaling. We hypothesized
that mTOR activation mechanisms driving oncogenesis can advise effective
therapeutic designs. To test this, we combined cancer genomic analysis
with extensive molecular dynamics simulations of mTOR oncogenic variants.
We observed that conformational changes within mTOR kinase domain
are associated with multiple mutational activation events. The mutations
disturb the α-packing formed by the kαAL, kα3, kα9,
kα9b, and kα10 helices in the kinase domain, creating
cryptic pocket. Its opening correlates with opening of the catalytic
cleft, including active site residues realignment, favoring catalysis.
The cryptic pocket created by disrupted α-packing coincides
with the allosteric pocket in PI3Kα can be harmoniously fitted
by the PI3Kα allosteric inhibitor RLY-2608, suggesting that
analogous drugs designed based on RLY-2608 can restore the packed
α-structure, resulting in mTOR inactive conformation. Our results
exemplify that knowledge of detailed kinase activation mechanisms
can inform innovative allosteric inhibitor development.