TIC10 (ONC201)

Catalog No.S7963

For research use only.

TIC10 (ONC201) inactivates Akt and ERK to induce TNF-related apoptosis-inducing ligand (TRAIL) through Foxo3a, possesses superior drug properties: delivery across the blood-brain barrier, superior stability and improved pharmacokinetics. Phase 1/2.

TIC10 (ONC201) Chemical Structure

CAS No. 1616632-77-9

Selleck's TIC10 (ONC201) has been cited by 8 Publications

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Description TIC10 (ONC201) inactivates Akt and ERK to induce TNF-related apoptosis-inducing ligand (TRAIL) through Foxo3a, possesses superior drug properties: delivery across the blood-brain barrier, superior stability and improved pharmacokinetics. Phase 1/2.
Targets
Akt [1] ERK [1]
In vitro

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. [1]

Assay
Methods Test Index PMID
Western blot Cleaved PARP / CC3 ; ATF4 / ATF3 ; p-GCN2 / GCN2 / p-eIF2a / eIF2a ; p-p70S6K / p-S6 / p-4EBP1 / 4EBP1 / p-HSF1 / HSF1 29588331 29588332 26884599
Growth inhibition assay Cell viability 29588330
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. [1]

Protocol (from reference)

Animal Research:[1]
  • Animal Models: Female athymic nu/nu mice
  • Dosages: 25, 50, 100 mg/kg
  • Administration: Intraperitoneal/oral

Solubility (25°C)

In vitro

DMSO 77 mg/mL warmed
(199.22 mM)
Ethanol 77 mg/mL warmed
(199.22 mM)
Water Insoluble

Chemical Information

Molecular Weight 386.49
Formula

C24H26N4O

CAS No. 1616632-77-9
Storage 3 years -20°C powder
2 years -80°C in solvent
Smiles CC1=CC=CC=C1CN2C(=O)C3=C(CCN(C3)CC4=CC=CC=C4)N5C2=NCC5

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Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

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Clinical Trial Information

NCT Number Recruitment Interventions Conditions Sponsor/Collaborators Start Date Phases
NCT04629209 Withdrawn Drug: ONC201 Glioblastoma Chimerix February 15 2021 Phase 2
NCT03932643 Recruiting Drug: ONC201 Acute Myeloid Leukemia|Myelodysplastic Syndromes Vijaya Bhatt|University of Nebraska July 30 2019 Phase 1
NCT03099499 Suspended Drug: ONC201 Endometrial Cancer Fox Chase Cancer Center|Oncoceutics Inc. June 8 2017 Phase 2
NCT02609230 Completed Drug: ONC-201 Advanced Solid Tumors|Multiple Myeloma Fox Chase Cancer Center November 5 2015 Phase 1

(data from https://clinicaltrials.gov, updated on 2022-01-17)

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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