CZ-415

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

一种有效、高选择性、ATP 竞争性、口服生物可利用的 mTOR 抑制剂，pKd 为 8.2。

A potent, highly selective, ATP-competitive and orally bioavailable mTOR inhibitor with pKd of 8.2; displays >100-fold selectivity over PI3Ks; inhibit downstream targets phosphorylation of pS6RP (S240/244) and pAkt (S473) in HEK293T cells with IC50 of 14.5 nM and 14.8 nM, inhibits IFNγ production in stimulated human whole blood with IC50 of 226 nM; shows efficacy in a semitherapeutic collagen induced arthritis (CIA) mouse model.

Inhibition of phosphorylation for both downstream targets results in 14.5 nM IC50 for pS6RP and 14.8 nM for pAKT. The immunosuppressive effect of CZ415 is measured by detecting secreted IFNγ after 18 hours in stimulated human whole blood and the resulting IC50 is 226 nM. As a predictor for cardiotoxicity, the activity of CZ415 against the human cardiac ion channel hERG is assessed in a whole-cell patch-clamp assay in HEK293 cells resulting in an IC50 of 48 μM.

CZ415 is a highly selective mTOR inhibitor showing in vivo efficacy in a collagen induced arthritis (CIA) model. For full characterization of CZ415 and to enable improved dose predictions, the pharmacokinetic (PK) profile is assessed in rat. PK and oral bioavailability are determined after of 1 mg/kg intravenous (iv) bolus and 3 mg/kg oral (po) administration. The observed plasma clearance, corresponding to 45% liver blood flow, suggests that sufficient levels of free compound are circulating in the animal over time. The oral uptake is rapid with a Tmaxmax of 0.5 h and bioavailability F = 44% indicates very good absorption from the gut.

CZ415

PI3K/Akt/mTOR signaling

mTOR

mTOR

Cancer

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1429639-50-8

459.5618

C22H29N5O4S

>98% (HPLC)

DMSO: ≥ 31 mg/mL

O=C(NCC)NC1=CC=C(C2=NC(N3[C@@H](C)COCC3)=C4C(C(C)(C)S(C4)(=O)=O)=N2)C=C1

Urea, N-[4-[5,7-dihydro-7,7-dimethyl-4-[(3S)-3-methyl-4-morpholinyl]-6,6-dioxidothieno[3,4-d]pyrimidin-2-yl]phenyl]-N'-ethyl-

(-20℃)

With Ice Pack

≥ 2 years