WYE-354

Research use only, not for human use.

WYE-354 is a potent, selective and ATP-competitive inhibitor of mTOR with IC50 of 5 nM (recombinant mTOR ).

WYE-354 is a potent, selective and ATP-competitive inhibitor of mTOR with IC50 of 5 nM (recombinant mTOR ), displays >100-fold selectivity over PI3K isofoms; acutely blocks substrate phosphorylation by mTORC1 and mTORC2 in vitro and in cells in response to growth factor, amino acids, and hyperactive PI3K/AKT, reduces AKT downstream function and inhibits proliferation of diverse cancer cell lines; inhibits mTORC1 and mTORC2 and displayed robust antitumor activity in PTEN-null tumors.

In the DELFIA measuring His6-S6K1 T389 phosphorylation, WYE-354 inhibits recombinant mTOR enzyme with an IC50 of 5 nM. Cell viability is analyzed by MTS assay. G-415 and TGBC-2TKB cell lines are treated with increasing concentrations of WYE-354 (0.1, 1, 5 and 10 μM) for 24, 48, and 72 hours. WYE-354 significantly reduces cell viability starting at a 1 μM concentration after a 24 hours exposure, in both studied cell lines (P<0.001). A decrease in cell viability is not observed at a dose of 100 nM, except for the TGBC-2TKB cell line after 72 hours of treatment.

The effect of Rapamycin and WYE-354 on tumor growth is evaluated in xenograft GBC tumor models. 2×106 or 5×106 cells of G-415 or TGBC2TKB, respectively, are xenotransplanted into NOD-SCID mice subcutaneously. When tumors reach an average volume of 100 mm3, the mice are treated either with Rapamycin or WYE354. Rapamycin is administered i.p. at a concentration of 10 mg/kg, daily for 5 days per week for 3 weeks, while WYE-354 is administrated at a daily i.p. dose of 50 mg/kg for 5 days. Mice are sacrificed 30 days after the initiation of the treatments and an autopsy is performed that include removal of the entire tumor area. Mice treated with WYE-354 exhibit 68.6% and 52.4% reduction in average tumor size (P<0.01; P<0.01), as well as 82.9% and 45.5% (P<0.01; ns) reduction in tumor weight, respectively.

WYE 354 | WYE354

PI3K/Akt/mTOR signaling

mTOR

GCK|Hck|mTOR|PI3Kα|PI3Kγ

Cancer

——

1062169-56-5

495.5309

C24H29N7O5

>98% (HPLC)

DMSO: ≥ 26 mg/mL

O=C(N1CCC(N2N=CC3=C(N4CCOCC4)N=C(C5=CC=C(NC(OC)=O)C=C5)N=C32)CC1)OC

1-Piperidinecarboxylic acid, 4-[6-[4-[(methoxycarbonyl)amino]phenyl]-4-(4-morpholinyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-, methyl ester

(-20℃)

With Ice Pack

≥ 2 years