ONC-201

Investigational

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 Search

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
Sources: http://adisinsight.springer.com/drugs/800039735https://www.ncbi.nlm.nih.gov/pubmed/23390247 | https://www.ncbi.nlm.nih.gov/pubmed/25587031 | https://www.scripps.edu/news/press/2014/20140519janda.html
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.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
response to stress 2 Target ID: GO:0006950 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27602582	Activator 1343
TRAIL-activated apoptotic signaling pathway 3 Target ID: GO:0036462 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23390247	Activator 1343
D2-like dopamine receptor 9 Target ID: CHEMBL2331075 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27602582	Antagonist 2575
Serine/threonine-protein kinase AKT 27 Target ID: CHEMBL4282 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23390247	Inhibitor 7728
Mitogen-activated protein kinase; ERK1/ERK2 4 Target ID: CHEMBL1907606 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23390247	Inhibitor 7728

Conditions

Condition	Modality	Highest Phase	Product
Glioblastoma 55 Sources: http://adisinsight.springer.com/drugs/800039735	Primary	Phase II 1101	Unknown Approved Use Unknown
Leukemia 82 Sources: http://adisinsight.springer.com/drugs/800039735	Primary	Phase II 1101	Unknown Approved Use Unknown
Non-Hodgkin's lymphoma 74 Sources: http://adisinsight.springer.com/drugs/800039735	Primary	Phase II 1101	Unknown Approved Use Unknown
Multiple myeloma 145 Sources: http://adisinsight.springer.com/drugs/800039735	Primary	Phase II 1101	Unknown Approved Use Unknown
Solid tumors 140 Sources: http://adisinsight.springer.com/drugs/800039735	Primary	Phase I 409	Unknown Approved Use Unknown
Lymphoma 57 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25587031	Primary	Preclinical	Unknown Approved Use Unknown
Colon cancer 61 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25587031	Primary	Preclinical	Unknown Approved Use Unknown
Triple-negative breast cancer 12 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25587031	Primary	Preclinical	Unknown Approved Use Unknown

C_max

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

T_1/2

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
substrate 1601 inhibitor 1467	substrate 936 inhibitor 1604	substrate 1118 inhibitor 1702

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
BCRP 643 CYP2B6 717 CYP2C8 818 CYP2C19 1325 P-gp 1330	Efflux transporters 3 CYP2B6 616 CYP2C8 634 CYP2C19 910	CYPs 10

Drug as perpetrator

Target	Modality	Activity
CYPs 26	inducer 1440 Sources: https://cancerres.aacrjournals.org/content/81/13_Supplement/1370.short	no
CYP2D6 1738	inhibitor 3045 Sources: https://cancerres.aacrjournals.org/content/81/13_Supplement/1370.short \| https://pubchem.ncbi.nlm.nih.gov/bioassay/1645840#sid=440681416	yes [IC50 11.9877 uM]
CYP3A4 1772	inhibitor 3045 Sources: https://cancerres.aacrjournals.org/content/81/13_Supplement/1370.short \| https://pubchem.ncbi.nlm.nih.gov/bioassay/1645841#sid=440681416	yes [IC50 11.9877 uM]
P-gp 1514	inhibitor 3045 Sources: https://cancerres.aacrjournals.org/content/81/13_Supplement/1370.short \| https://pubchem.ncbi.nlm.nih.gov/bioassay/1346987#sid=363680432	yes [IC50 2.9093 uM]
CYP2C9 1648	inhibitor 3045 Sources: https://cancerres.aacrjournals.org/content/81/13_Supplement/1370.short \| https://pubchem.ncbi.nlm.nih.gov/bioassay/1645842#sid=440681416	yes [IC50 30.1116 uM]
BCRP 713	inhibitor 3045 Sources: https://cancerres.aacrjournals.org/content/81/13_Supplement/1370.short	yes
CYP2B6 884	inhibitor 3045 Sources: https://cancerres.aacrjournals.org/content/81/13_Supplement/1370.short	yes
CYP2C19 1392	inhibitor 3045 Sources: https://cancerres.aacrjournals.org/content/81/13_Supplement/1370.short	yes
CYP2C8 865	inhibitor 3045 Sources: https://cancerres.aacrjournals.org/content/81/13_Supplement/1370.short	yes

Drug as victim

Target	Modality	Activity
Efflux transporters 3	substrate 3113 Sources: https://cancerres.aacrjournals.org/content/81/13_Supplement/1370.short	no
CYP2B6 616	substrate 3113 Sources: https://cancerres.aacrjournals.org/content/81/13_Supplement/1370.short	yes
CYP2C19 910	substrate 3113 Sources: https://cancerres.aacrjournals.org/content/81/13_Supplement/1370.short	yes
CYP2C8 634	substrate 3113 Sources: https://cancerres.aacrjournals.org/content/81/13_Supplement/1370.short	yes
CYP2C9 936	substrate 3113 Sources: https://cancerres.aacrjournals.org/content/81/13_Supplement/1370.short	yes
CYP2D6 1118	substrate 3113 Sources: https://cancerres.aacrjournals.org/content/81/13_Supplement/1370.short	yes
CYP3A4 1601	substrate 3113 Sources: https://cancerres.aacrjournals.org/content/81/13_Supplement/1370.short	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	23390247
Pharmacophore reassignment for induction of the immunosurveillance cytokine TRAIL.	2014 Jun 23	24838721
ONC201 induces cell death in pediatric non-Hodgkin's lymphoma cells.	2015 Aug 3	26030065
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	26474387
ONC201 kills solid tumor cells by triggering an integrated stress response dependent on ATF4 activation by specific eIF2α kinases.	2016 Feb 16	26884600
mTOR inhibition sensitizes ONC201-induced anti-colorectal cancer cell activity.	2016 Sep 30	27565731

Patents

Sample Use Guides

In Vivo Use Guide

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

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