mTOR variants activation discovers PI3K-like cryptic pocket, expanding allosteric, mutant-selective inhibitor designs

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• The mechanistic target of rapamycin (mTOR) is a central regulator in the PI3K/AKT/mTOR signaling pathway.
• Dysregulation of mTOR signaling is implicated in various cancers, highlighting its role in oncogenesis.

Purpose of the Study:

• To investigate the molecular mechanisms underlying mTOR activation in cancer.
• To explore how understanding these mechanisms can inform the design of novel therapeutic strategies.

Main Methods:

• Utilized cancer genomic analysis to identify oncogenic mTOR variants.
• Employed extensive molecular dynamics simulations to study mTOR conformational changes.

Main Results:

• Observed that mutations in mTOR kinase domain induce conformational changes, disrupting alpha-helix packing and creating a cryptic pocket.
• This pocket's opening correlates with catalytic cleft opening and increased kinase activity.
• The identified cryptic pocket shares similarities with the PI3Kα allosteric pocket, suggesting potential for targeted inhibition.

Conclusions:

• Detailed understanding of mTOR activation mechanisms, particularly cryptic pocket formation, can guide the development of innovative allosteric inhibitors.
• Drugs analogous to PI3Kα inhibitors, like RLY-2608, could potentially restore mTOR's inactive conformation by stabilizing the alpha-helix structure.