MTOR INHIBITOR XIII ETP-46464

General description

A cell-permeable quinoline-containing heterotricyclic compound that acts as a potent inhibitor against mTOR, ATR, DNA-PK, PI 3-Kα, and ATM (IC₅₀ = 0.6, 14, 36, 170, and 545 nM, respectively) and preferentially suppresses radiation-induced cellular ATR activity (>90% at 500 nM) over ATM or DNA-PK activity (IC₅₀ >5 M) in U2OS cells, while exhibiting much reduced or little potency toward a panel of 26 other kinases (>55% inhibition at 5 M). Shown to synergize with UCN-01 (Cat. No. 539644) in replicative stress induction in S-phase replicating U2OS (1.5-, 61-, and 190-fold of control RS, respectively, with 1 M ETP-46464, 50 nM UCN-01, or combined treatment).

Please note that the molecular weight for this compound is batch-specific due to variable water content. Please refer to the vial label or the certificate of analysis for the batch-specific molecular weight. The molecular weight provided represents the baseline molecular weight without water.

A cell-permeable quinoline-containing heterotricyclic compound that acts as a potent inhibitor against mTOR, ATR, DNA-PK, PI 3-Kα, and ATM activity (IC₅₀ = 0.6, 14, 36, 170, and 545 nM, respectively, in cell-free kinase assays) and preferentially suppresses ionization radiation/IR-induced cellular ATR activity (>90% inhibition of IR-induced Chk1 pSer345 at 500 nM) over ATM or DNA-PK activity (IC₅₀ >5 µM against IR-induced ATM pSer189, Chk2 pThr68, DNA-PKcs pSer2056, and γH2AX) in U2OS cells, while exhibiting much reduced or little potency toward a panel of 26 other kinases (>55% inhibition at 5 µM). Shown to synergize with UCN-01 (Cat. No. 539644) in replicative stress/RS induction in S-phase replicating U2OS (% population with pan-nuclear γH2AX staining = 6.0% and 0.2%, respectively, with or without 8 h 5 µM ETP-46464 treatment; 1.5-, 61-, and 190-fold of control RS, respectively, with 1 µM ETP-46464 alone, 50 nM UCN-01 alone, or combined treatment). Likewise, ETP-46464 is also demonstrated to further enhance oncogenic mutations-caused RS elevation in MEF cultures (% RS population without/with 5 µM ETP-46464 treatment = 0.3/0.6, 1.3/2.5, 0.9/3.0, 3.9/11.4, respectively, in wt, p53^-/-, Cyclin E-transfected wt, and Cyclin E-transfected p53^-/- MEF).

Biochem/physiol Actions

Cell permeable: yes

Primary Target
ATR

Reversible: yes

Packaging

Packaged under inert gas

Warning

Toxicity: Standard Handling (A)

Reconstitution

Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 3 months at -20°C.

Other Notes

Thanasoula, M., et al. 2012. EMBO J.31, 3398.
Toledo, L.I., et al. 2011. Nat Struct Mol Biol.18, 721.

Legal Information

CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany