2 research outputs found
Selective ATP-Competitive Inhibitors of TOR Suppress Rapamycin-Insensitive Function of TORC2 in <i>Saccharomyces cerevisiae</i>
The target of rapamycin (TOR) is a critical regulator
of growth,
survival, and energy metabolism. The allosteric TORC1 inhibitor rapamycin
has been used extensively to elucidate the TOR related signal pathway
but is limited by its inability to inhibit TORC2. We used an unbiased
cell proliferation assay of a kinase inhibitor library to discover
QL-IX-55 as a potent inhibitor of S. <i>cerevisiae</i> growth.
The functional target of QL-IX-55 is the ATP-binding site of TOR2
as evidenced by the discovery of resistant alleles of TOR2 through
rational design and unbiased selection strategies. QL-IX-55 is capable
of potently inhibiting both TOR complex 1 and 2 (TORC1 and TORC2)
as demonstrated by biochemical IP kinase assays (IC<sub>50</sub> <50
nM) and cellular assays for inhibition of substrate YPK1 phosphorylation.
In contrast to rapamycin, QL-IX-55 is capable of inhibiting TORC2-dependent
transcription, which suggests that this compound will be a powerful
probe to dissect the Tor2/TORC2-related signaling pathway in yeast
Selective ATP-Competitive Inhibitors of TOR Suppress Rapamycin-Insensitive Function of TORC2 in <i>Saccharomyces cerevisiae</i>
The target of rapamycin (TOR) is a critical regulator
of growth,
survival, and energy metabolism. The allosteric TORC1 inhibitor rapamycin
has been used extensively to elucidate the TOR related signal pathway
but is limited by its inability to inhibit TORC2. We used an unbiased
cell proliferation assay of a kinase inhibitor library to discover
QL-IX-55 as a potent inhibitor of S. <i>cerevisiae</i> growth.
The functional target of QL-IX-55 is the ATP-binding site of TOR2
as evidenced by the discovery of resistant alleles of TOR2 through
rational design and unbiased selection strategies. QL-IX-55 is capable
of potently inhibiting both TOR complex 1 and 2 (TORC1 and TORC2)
as demonstrated by biochemical IP kinase assays (IC<sub>50</sub> <50
nM) and cellular assays for inhibition of substrate YPK1 phosphorylation.
In contrast to rapamycin, QL-IX-55 is capable of inhibiting TORC2-dependent
transcription, which suggests that this compound will be a powerful
probe to dissect the Tor2/TORC2-related signaling pathway in yeast