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Ref Type Journal Article
PMID (19209957)
Authors Feldman ME, Apsel B, Uotila A, Loewith R, Knight ZA, Ruggero D, Shokat KM
Title Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2.
Journal PLoS biology
Vol 7
Issue 2
Date 2009 Feb 10
URL
Abstract Text The mammalian target of rapamycin (mTOR) regulates cell growth and survival by integrating nutrient and hormonal signals. These signaling functions are distributed between at least two distinct mTOR protein complexes: mTORC1 and mTORC2. mTORC1 is sensitive to the selective inhibitor rapamycin and activated by growth factor stimulation via the canonical phosphoinositide 3-kinase (PI3K)-->Akt-->mTOR pathway. Activated mTORC1 kinase up-regulates protein synthesis by phosphorylating key regulators of mRNA translation. By contrast, mTORC2 is resistant to rapamycin. Genetic studies have suggested that mTORC2 may phosphorylate Akt at S473, one of two phosphorylation sites required for Akt activation; this has been controversial, in part because RNA interference and gene knockouts produce distinct Akt phospho-isoforms. The central role of mTOR in controlling key cellular growth and survival pathways has sparked interest in discovering mTOR inhibitors that bind to the ATP site and therefore target both mTORC2 and mTORC1. We investigated mTOR signaling in cells and animals with two novel and specific mTOR kinase domain inhibitors (TORKinibs). Unlike rapamycin, these TORKinibs (PP242 and PP30) inhibit mTORC2, and we use them to show that pharmacological inhibition of mTOR blocks the phosphorylation of Akt at S473 and prevents its full activation. Furthermore, we show that TORKinibs inhibit proliferation of primary cells more completely than rapamycin. Surprisingly, we find that mTORC2 is not the basis for this enhanced activity, and we show that the TORKinib PP242 is a more effective mTORC1 inhibitor than rapamycin. Importantly, at the molecular level, PP242 inhibits cap-dependent translation under conditions in which rapamycin has no effect. Our findings identify new functional features of mTORC1 that are resistant to rapamycin but are effectively targeted by TORKinibs. These potent new pharmacological agents complement rapamycin in the study of mTOR and its role in normal physiology and human disease.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
PP30 PP30 1 0
Torin 1 Torin 1 1 0
Torkinib Torkinib 3 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
PP30 mTOR Inhibitor 51 PP30 inhibits mTOR signaling through mTORC1 and mTORC2, thereby preventing cell proliferation (PMID: 19209957).
Torin 1 mTOR Inhibitor 51 Torin 1 inhibits mTOR signaling through mTORC1 and mTORC2, thereby preventing cell proliferation (PMID: 19209957, PMID: 29063293).
Torkinib PP242 mTOR Inhibitor 51 Torkinib (PP242) inhibits mTOR signaling through mTORC1/2, thereby preventing cell proliferation (PMID: 19209957).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown Indication other than cancer not applicable PP30 Preclinical Actionable In a preclinical study, PP30 inhibited proliferation of mouse embryonic fibroblasts more effectively than rapamycin (PMID: 19209957). 19209957