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|Ref Type||Journal Article|
|Authors||Yu K, Toral-Barza L, Shi C, Zhang WG, Lucas J, Shor B, Kim J, Verheijen J, Curran K, Malwitz DJ, Cole DC, Ellingboe J, Ayral-Kaloustian S, Mansour TS, Gibbons JJ, Abraham RT, Nowak P, Zask A|
|Title||Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin.|
|Date||2009 Aug 1|
|Abstract Text||The mammalian target of rapamycin (mTOR) is centrally involved in cell growth, metabolism, and angiogenesis. While showing clinical efficacy in a subset of tumors, rapamycin and rapalogs are specific and allosteric inhibitors of mTOR complex 1 (mTORC1), but they do not directly inhibit mTOR complex 2 (mTORC2), an emerging player in cancer. Here, we report chemical structure and biological characterization of three pyrazolopyrimidine ATP-competitive mTOR inhibitors, WAY-600, WYE-687, and WYE-354 (IC(50), 5-9 nmol/L), with significant selectivity over phosphatidylinositol 3-kinase (PI3K) isofoms (>100-fold). Unlike the rapalogs, these inhibitors acutely blocked substrate phosphorylation by mTORC1 and mTORC2 in vitro and in cells in response to growth factor, amino acids, and hyperactive PI3K/AKT. Unlike the inhibitors of PI3K or dual-pan PI3K/mTOR, cellular inhibition of P-S6K1(T389) and P-AKT(S473) by the pyrazolopyrimidines occurred at significantly lower inhibitor concentrations than those of P-AKT(T308) (PI3K-PDK1 readout), showing mTOR selectivity in cellular setting. mTOR kinase inhibitors reduced AKT downstream function and inhibited proliferation of diverse cancer cell lines. These effects correlated with a strong G(1) cell cycle arrest in both the rapamycin-sensitive and rapamycin-resistant cells, selective induction of apoptosis, repression of global protein synthesis, and down-regulation of angiogenic factors. When injected into tumor-bearing mice, WYE-354 inhibited mTORC1 and mTORC2 and displayed robust antitumor activity in PTEN-null tumors. Together, our results highlight mechanistic differentiation between rapalogs and mTOR kinase inhibitors in targeting cancer cell growth and survival and provide support for clinical development of mTOR kinase inhibitors as new cancer therapy.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|WAY-600||WAY 600||mTOR Inhibitor 51||WAY-600 inhibits mTOR signaling through mTORC1 and mTORC2, thereby promoting cell cycle arrest and apoptosis (PMID: 19584280, PMID: 27107695).|
|WYE-354||WYE 354||mTOR Inhibitor 51||WYE-354 inhibits mTOR signaling through mTORC1 and mTORC2, thereby promoting cell cycle arrest and apoptosis (PMID: 19584280, PMID: 32092870).|
|WYE-687||WYE 687||mTOR Inhibitor 51||WYE-687 inhibits mTOR signaling through mTORC1 and mTORC2, thereby promoting cell cycle arrest and apoptosis (PMID: 19584280, PMID: 28257457, PMID: 26792718).|
|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||colorectal cancer||not applicable||WYE-354||Preclinical||Actionable||In a preclinical study, WYE-354 induced cell cycle arrest and inhibited cell proliferation of colorectal cancer cells in culture (PMID: 19584280).||19584280|
|Unknown unknown||colorectal cancer||not applicable||WYE-687||Preclinical||Actionable||In a preclinical study, WYE-687 induced cell cycle arrest and inhibited cell proliferation of colorectal cancer cells in culture (PMID: 19584280).||19584280|
|Unknown unknown||colorectal cancer||not applicable||WAY-600||Preclinical||Actionable||In a preclinical study, WAY-600 induced cell cycle arrest and inhibited cell proliferation of colorectal cancer cells in culture (PMID: 19584280).||19584280|