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Details

Stereochemistry ACHIRAL
Molecular Formula C24H26N4O
Molecular Weight 386.4903
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of ONC-201

SMILES

Cc1ccccc1CN2C(=O)C3=C(CCN(Cc4ccccc4)C3)N5CCN=C52

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

HIDE SMILES / InChI

Molecular Formula C24H26N4O
Molecular Weight 386.4903
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Description
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 (TIC10 isomer or ONC201 isomer) is a potent, orally active, and stable small molecule and is an efficacious antitumor therapeutic agent that acts on tumor cells and their microenvironment to enhance the concentrations of the endogenous tumor necrosis factor-related apoptosis-inducing 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 TIC10 isomer. TIC10 transcriptionally induces a sustained up-regulation TRAIL in tumors and normal cells in a p53-independent manner. 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 crosses the blood-brain barrier. TIC10 treatment caused tumor regression in the HCT116 p53−/− xenograft, RKO human colon cancer xenograft–bearing mice and human triple-negative breast cancer xenografts and significantly prolonged the survival of Eμ-myc transgenic mice, which spontaneously develop metastatic lymphoma from weeks 9 to 12 of age by 4 weeks.

Approval Year

TargetsConditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
3.6 μg/mL
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

AUC

ValueDoseCo-administeredAnalytePopulation
37.7 μg × h/mL
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

T1/2

ValueDoseCo-administeredAnalytePopulation
11.3 h
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
OverviewDrug as perpetrator​Drug as victim
PubMed

PubMed

TitleDatePubMed
Dual inactivation of Akt and ERK by TIC10 signals Foxo3a nuclear translocation, TRAIL gene induction, and potent antitumor effects.
2013 Feb 6
Pharmacophore reassignment for induction of the immunosurveillance cytokine TRAIL.
2014 Jun 23
ONC201 induces cell death in pediatric non-Hodgkin's lymphoma cells.
2015 Aug 3
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
ONC201 kills solid tumor cells by triggering an integrated stress response dependent on ATF4 activation by specific eIF2α kinases.
2016 Feb 16
mTOR inhibition sensitizes ONC201-induced anti-colorectal cancer cell activity.
2016 Sep 30
Patents

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
5-10 uM TIC10 induces TRAIL-mediated apoptosis in p53 deficient HCT116 cells.
Substance Class Chemical
Created
by admin
on Sat Jun 26 01:33:44 UTC 2021
Edited
by admin
on Sat Jun 26 01:33:44 UTC 2021
Record UNII
9U35A31JAI
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
ONC-201
Common Name English
ONC201
Code English
TIC-10
Code English
ONC 201 [WHO-DD]
Common Name English
IMIDAZO(1,2-A)PYRIDO(3,4-E)PYRIMIDIN-5(1H)-ONE, 2,4,6,7,8,9-HEXAHYDRO-4-((2-METHYLPHENYL)METHYL)-7-(PHENYLMETHYL)-
Systematic Name English
TIC10
Code English
2,4,6,7,8,9-HEXAHYDRO-4-((2-METHYLPHENYL)METHYL)-7-(PHENYLMETHYL)IMIDAZO(1,2-A)PYRIDO(3,4-E)PYRIMIDIN-5(1H)-ONE
Systematic Name English
NSC-350625
Code English
Classification Tree Code System Code
FDA ORPHAN DRUG 553316
Created by admin on Sat Jun 26 01:33:44 UTC 2021 , Edited by admin on Sat Jun 26 01:33:44 UTC 2021
FDA ORPHAN DRUG 640218
Created by admin on Sat Jun 26 01:33:44 UTC 2021 , Edited by admin on Sat Jun 26 01:33:44 UTC 2021
Code System Code Type Description
CAS
1342897-86-2
Created by admin on Sat Jun 26 01:33:44 UTC 2021 , Edited by admin on Sat Jun 26 01:33:44 UTC 2021
NO STRUCTURE GIVEN
PUBCHEM
73777259
Created by admin on Sat Jun 26 01:33:44 UTC 2021 , Edited by admin on Sat Jun 26 01:33:44 UTC 2021
PRIMARY
FDA UNII
9U35A31JAI
Created by admin on Sat Jun 26 01:33:44 UTC 2021 , Edited by admin on Sat Jun 26 01:33:44 UTC 2021
PRIMARY
CAS
1616632-77-9
Created by admin on Sat Jun 26 01:33:44 UTC 2021 , Edited by admin on Sat Jun 26 01:33:44 UTC 2021
PRIMARY
DRUG BANK
DB14844
Created by admin on Sat Jun 26 01:33:44 UTC 2021 , Edited by admin on Sat Jun 26 01:33:44 UTC 2021
PRIMARY
Related Record Type Details
SALT/SOLVATE -> PARENT
TARGET -> INHIBITOR
ANTAGONIST
Related Record Type Details
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.
ACTIVE MOIETY
Drug: ONC-201(Primary) Indication: Solid tumours Focus: Pharmacokinetics Most Recent Events: 30 Jul 2015 New trial record