Details
Stereochemistry | ACHIRAL |
Molecular Formula | C24H26N4O.2ClH |
Molecular Weight | 459.411 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
Cl.Cl.CC1=CC=CC=C1CN2C3=NCCN3C4=C(CN(CC5=CC=CC=C5)CC4)C2=O
InChI
InChIKey=HKBXPCQCBQFDML-UHFFFAOYSA-N
InChI=1S/C24H26N4O.2ClH/c1-18-7-5-6-10-20(18)16-28-23(29)21-17-26(15-19-8-3-2-4-9-19)13-11-22(21)27-14-12-25-24(27)28;;/h2-10H,11-17H2,1H3;2*1H
DescriptionSources: http://adisinsight.springer.com/drugs/800039735Curator's Comment: Description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/27602582 | https://www.ncbi.nlm.nih.gov/pubmed/25859547 | https://www.ncbi.nlm.nih.gov/pubmed/23390247 | https://www.ncbi.nlm.nih.gov/pubmed/25587031 | https://www.ncbi.nlm.nih.gov/pubmed/24838721
Sources: http://adisinsight.springer.com/drugs/800039735
Curator's Comment: Description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/27602582 | https://www.ncbi.nlm.nih.gov/pubmed/25859547 | https://www.ncbi.nlm.nih.gov/pubmed/23390247 | https://www.ncbi.nlm.nih.gov/pubmed/25587031 | https://www.ncbi.nlm.nih.gov/pubmed/24838721
TIC10 (NSC350625 or ONC201) is a small-molecule compound belongs to a chemical class known as imipridones, that possess a unique three-ring heterocycle with two substitutable basic amines. ONC201 has anti-proliferative and pro-apoptotic effects against a broad range of tumor cells but not normal cells. The mechanism of action of ONC201 involves engagement of PERK-independent activation of the integrated stress response, leading to tumor upregulation of DR5 and dual Akt/ERK inactivation, and consequent Foxo3a activation leading to upregulation of the death ligand TRAIL. The isomeric structure of TIC10/ONC201 is critical to its activity: anti-cancer activity is associated with the angular structure and not the linear isomer. Clinical trials are evaluating the single agent efficacy of ONC201 in multiple solid tumors and hematological malignancies and exploring alternative dosing regimens. Oncoceutics is developing ONC 201 as a potential therapy for treatment of p53-deficient cancers (including solid tumours).
Originator
Sources: https://www.ncbi.nlm.nih.gov/pubmed/23390247 | http://adisinsight.springer.com/drugs/800039735
Curator's Comment: Allen et al., 2013; Oncoceutics, Inc.
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
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Target ID: GO:0006950 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27602582 |
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Target ID: GO:0036462 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23390247 |
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Target ID: CHEMBL2331075 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27602582 |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
Cmax
Value | Dose | Co-administered | Analyte | Population |
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3.6 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28331050/ |
625 mg 1 times / 3 weeks multiple, oral dose: 625 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
ONC201 plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
AUC
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
37.7 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28331050/ |
625 mg 1 times / 3 weeks multiple, oral dose: 625 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
ONC201 plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
T1/2
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
11.3 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28331050/ |
625 mg 1 times / 3 weeks multiple, oral dose: 625 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
ONC201 plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
OverviewOther
Other Inhibitor | Other Substrate | Other Inducer |
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Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
no | ||||
yes [IC50 11.9877 uM] | ||||
yes [IC50 11.9877 uM] | ||||
yes [IC50 2.9093 uM] | ||||
yes [IC50 30.1116 uM] | ||||
yes | ||||
yes | ||||
yes | ||||
yes |
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
no | ||||
yes | ||||
yes | ||||
yes | ||||
yes | ||||
yes | ||||
yes |
PubMed
Title | Date | PubMed |
---|---|---|
Dual inactivation of Akt and ERK by TIC10 signals Foxo3a nuclear translocation, TRAIL gene induction, and potent antitumor effects. | 2013 Feb 6 |
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The angular structure of ONC201, a TRAIL pathway-inducing compound, determines its potent anti-cancer activity. | 2014 Dec 30 |
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Pharmacophore reassignment for induction of the immunosurveillance cytokine TRAIL. | 2014 Jun 23 |
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TIC10/ONC201: a bend in the road to clinical development. | 2015 |
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Genetic and Pharmacological Screens Converge in Identifying FLIP, BCL2, and IAP Proteins as Key Regulators of Sensitivity to the TRAIL-Inducing Anticancer Agent ONC201/TIC10. | 2015 Apr 15 |
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ONC201: Stressing tumors to death. | 2016 Feb 16 |
Sample Use Guides
The first-in-human clinical trial of ONC201 in advanced aggressive refractory solid tumors confirmed that ONC201 is exceptionally well-tolerated and established the recommended phase II dose of 625 mg administered orally every three weeks defined by drug exposure comparable to efficacious levels in preclinical models.
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/23390247
5-10 uM TIC10 induces TRAIL-mediated apoptosis in p53 deficient HCT116 cells.
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FDA ORPHAN DRUG |
527916
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ACTIVE MOIETY
SUBSTANCE RECORD