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Description: TIC10 (ONC-201, NSC-350625), an imipridone compound, is a novel, potent, orally bioavailable, brain/BBB penetrant, and stable tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) inducer with potential anticancer activity. It was initially developed in the 1970s as an anti-seizure agent which acts by inhibiting Akt and ERK, consequently activating Foxo3a and significantly inducing cell surface TRAIL. TIC10 can inactivate Akt and ERK to induce TRAIL through Foxo3a, possesses superior drug properties: delivery across the blood-brain barrier, superior stability and improved pharmacokinetics. TIC10 is a potent, orally active, and stable small molecule that transcriptionally induces TRAIL in a p53-independent manner. TIC10 induces a sustained up-regulation of TRAIL in tumors and normal cells that may contribute to the demonstrable antitumor activity of TIC10.
References:Cancer Res. 2015 Apr 15;75(8):1668-74; Sci Transl Med. 2013 Feb 6;5(171):171ra17.
Related CAS #: 1616632-77-9 (free base); 1638178-82-1 (HCl); 41276-02-2 (TIC10 analog); 1777785-71-3 (HBr) 2007141-57-1 (2HBr) 41276-02-2 (TIC10 isomer)
2023-2024产品目录
产品使用说明书(通用型)
Chemical Name: 7-benzyl-4-(2-methylbenzyl)-1,2,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(4H)-one
SMILES Code: O=C1N(CC2=CC=CC=C2C)C3=NCCN3C4=C1CN(CC5=CC=CC=C5)CC4
Mass (g) = Concentration (mol/L) × Volume (L) × Molecular Weight (g/mol)
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
This equation is commonly abbreviated as: C1V1 = C2V2
In Vitro
In Vitro Assay: TIC10 transcriptionally induces TRAIL in a p53-independent manner and crosses the blood-brain barrier. TIC10 induces a sustained up-regulation of TRAIL in tumors and normal cells that may contribute to the demonstrable antitumor activity of TIC10. TIC10 inactivates kinases Akt and extracellular signal-regulated kinase (ERK), leading to the translocation of Foxo3a into the nucleus, where it binds to the TRAIL promoter to up-regulate gene transcription. TIC10 is an efficacious antitumor therapeutic agent that acts on tumor cells and their micro-environment to enhance the concentrations of the endogenous tumor suppressor TRAIL. TIC10 also causes a down-regulation of the total expression of ERK.
Cell Assay: TIC10 causes a dose-dependent increase in TRAIL mRNA and induces TRAIL protein localization on the cell surface of several cancer cell lines in a p53-independent manner. TIC10 has broad-spectrum activity against multiple malignancies in vitro and induces an increase in sub-G1 DNA content suggestive of cell death in TRAIL-sensitive HCT116 p53−/− cells, but does not alter the cell cycle profiles of normal fibroblasts at equivalent doses. TIC10 decreases the clonogenic survival of cancer cell lines and spares normal fibroblasts. TIC10 increases the percentage of sub-G1 DNA in cancer cells in a p53-independent and Bax-dependent manner, as previously reported for TRAIL-mediated apoptosis. TIC10-induced TRAIL up-regulation is Foxo3a-dependent, which also up-regulates TRAIL death receptor DR5 among other targets, potentially allowing for sensitization of some TRAIL-resistant tumor cells. TIC10 inactivates kinases Akt and extracellular signal–regulated kinase (ERK), leading to the translocation of Foxo3a into the nucleus, where it binds to the TRAIL promoter to up-regulate gene transcription. TIC10 is an efficacious antitumor therapeutic agent that acts on tumor cells and their microenvironment to enhance the concentrations of the endogenous tumor suppressor TRAIL.
In Vivo
TIC10 and TRAIL treatment causes tumor regression in the HCT116 p53−/− xenograft to a comparable extent when both are administered as multiple doses. TIC10 also induces regression of MDA-MB-231 human triple-negative breast cancer xenografts, whereas TRAIL-treated tumors progressed. In DLD-1 colon cancer xenografts, TIC10 induces tumor stasis at 1 week after treatment, whereas TRAIL-treated tumors progresses after a single dose. A single dose of TIC10 also induces a sustained regression of the SW480 xenograft and is equally effective when delivered by intraperitoneal or oral route, suggesting favorable oral bioavailability for TIC10. TIC10 causes tumor-specific cell death by TRAIL-mediated direct and bystander effects. TIC10 is an effective antitumor agent against orthotopic human glioblastoma multiforme tumors.
Animal model
Female athymic nu/nu mice
Formulation & Dosage
Dissolved in DMSO; 25, 50, 100 mg/kg; p.o./i.p.
References
[1] Allen JE, et al. Sci Transl Med, 2013, 5(171), 171ra17.
Purity ≥98%
COA
MSDS
NMR
TIC10 is a small molecule that induces TRAIL independent of p53. Sci Transl Med, 2013, 5(171), 171ra17.
TIC10 induces TRAIL in tumor and normal cells.
TIC10 is effective as an antitumor agent in GBM.