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Selective ATP-competitive inhibitors of TOR suppress rapamycin-insensitive function of TORC2 in Saccharomyces

Qingsong Liu, Tao Ren, Tara Fresques

    ACS Chemical Biology
    |April 13, 2012
    PubMed

    Insights

    Scientists discovered QL-IX-55, a novel inhibitor targeting both TORC1 and TORC2 complexes in yeast. This compound offers a powerful new tool for studying the Tor2/TORC2 signaling pathway, overcoming limitations of existing drugs like rapamycin.

    Area of Science:

    • Cell Biology
    • Biochemistry
    • Molecular Biology

    Background:

    • The target of rapamycin (TOR) pathway is crucial for regulating cell growth, survival, and metabolism.
    • Rapamycin, an allosteric inhibitor, effectively targets TORC1 but cannot inhibit TORC2, limiting its utility in studying TORC2 signaling.
    • Understanding TORC2 function requires novel inhibitors that can effectively block its activity.

    Discussion:

    • QL-IX-55 was identified through an unbiased screen of kinase inhibitors as a potent inhibitor of Saccharomyces cerevisiae growth.
    • Resistance studies revealed that QL-IX-55 targets the ATP-binding site of TOR2.
    • QL-IX-55 demonstrates potent inhibition of both TORC1 and TORC2, with IC(50) values below 50 nM in biochemical assays.

    Key Insights:

    • QL-IX-55 effectively inhibits TORC1 and TORC2, unlike rapamycin.
    • The compound inhibits TORC2-dependent transcription, a function not achieved by rapamycin.
    • Biochemical and cellular assays confirm QL-IX-55's potent inhibition of TOR kinase activity and substrate phosphorylation.

    Outlook:

    • QL-IX-55 serves as a valuable chemical probe for dissecting the Tor2/TORC2 signaling pathway in yeast.
    • This inhibitor's ability to block both TOR complexes opens new avenues for research into TOR-mediated cellular processes.
    • Further studies using QL-IX-55 can elucidate the specific roles of TORC2 in various cellular functions and potentially in disease states.

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