Details
Stereochemistry | ACHIRAL |
Molecular Formula | C24H26N4O |
Molecular Weight | 386.4894 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
CC1=CC=CC=C1CN2C3=NCCN3C4=C(CN(CC5=CC=CC=C5)CC4)C2=O
InChI
InChIKey=VLULRUCCHYVXOH-UHFFFAOYSA-N
InChI=1S/C24H26N4O/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
Molecular Formula | C24H26N4O |
Molecular Weight | 386.4894 |
Charge | 0 |
Count |
|
Stereochemistry | ACHIRAL |
Additional Stereochemistry | No |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Optical Activity | NONE |
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 |
---|---|---|---|
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 |
---|---|---|---|---|
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 |
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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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Small-Molecule ONC201/TIC10 Targets Chemotherapy-Resistant Colorectal Cancer Stem-like Cells in an Akt/Foxo3a/TRAIL-Dependent Manner. | 2015 Apr 1 |
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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 induces cell death in pediatric non-Hodgkin's lymphoma cells. | 2015 Aug 3 |
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Identification of TRAIL-inducing compounds highlights small molecule ONC201/TIC10 as a unique anti-cancer agent that activates the TRAIL pathway. | 2015 May 1 |
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TIC10/ONC201 synergizes with Bcl-2/Bcl-xL inhibition in glioblastoma by suppression of Mcl-1 and its binding partners in vitro and in vivo. | 2015 Nov 3 |
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The preclinical evaluation of TIC10/ONC201 as an anti-pancreatic cancer agent. | 2016 Aug 5 |
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ONC201 kills solid tumor cells by triggering an integrated stress response dependent on ATF4 activation by specific eIF2α kinases. | 2016 Feb 16 |
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ATF4 induction through an atypical integrated stress response to ONC201 triggers p53-independent apoptosis in hematological malignancies. | 2016 Feb 16 |
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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.
Substance Class |
Chemical
Created
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admin
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Edited
Sat Dec 16 20:21:39 GMT 2023
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Sat Dec 16 20:21:39 GMT 2023
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Record UNII |
9U35A31JAI
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Record Status |
Validated (UNII)
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FDA ORPHAN DRUG |
553316
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FDA ORPHAN DRUG |
640218
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LM-148
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1342897-86-2
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C113792
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73777259
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9U35A31JAI
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1616632-77-9
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DB14844
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350625
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Related Record | Type | Details | ||
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SALT/SOLVATE -> PARENT |
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TARGET -> INHIBITOR |
ANTAGONIST
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ACTIVE MOIETY |
Experiments showed that TIC10 had potent effects against a variety of tumours, including breast, lymphatic, colon and lung cancer. It was especially effective at triggering cell suicide in glioblastoma, a kind of brain tumour that is notoriously difficult to treat2. Mice with glioblastomas that were treated with TIC10 in combination with bevacizumab a drug used against diseases including brain tumours, and sold under the name Avastin survived three times as long as untreated mice. Even mice treated with TIC-10 alone still had better survival rates (6% longer) than those treated with bevacizumab alone.
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