ArticleJournal of chemical information and modeling2025
mTOR Variants Activation Discovers PI3K-like Cryptic Pocket, Expanding Allosteric, Mutant-Selective Inhibitor Designs.
Article in Journal of chemical information and modeling, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
7 citing papers in PubMed.
- Targeting "undruggable" cancer proteins: pharmacological challenges and emerging strategies.Translational cancer research · 2026Review
- Allosteric drugs in biomolecular condensates: ways forward.Drug discovery today · 2026Review
- Leveraging conformational ensembles in allosteric drug discovery.Trends in pharmacological sciences · 2026Review
- Condensates and cell states: A new paradigm for understanding tumor biology.Biophysical journal · 2026Review
- Oncogenic PI3Kα variants reveal graded conformational spectrum with mutation-specific cryptic pockets.Communications chemistry · 2026Article
- Uncovering the molecular basis of kinase activity and substrate recognition with phospho-PCA.bioRxiv : the preprint server for biology · 2025Article
- Allostery in Disease: Anticancer Drugs, Pockets, and the Tumor Heterogeneity Challenge.Journal of molecular biology · 2025Review
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Authors and funding
4 authors.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.