Dordaviprone

Investigational

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

Structure Search

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

HIDE SMILES / InChI

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

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 3 Target ID: GO:0006950 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27602582	Activator 1447
TRAIL-activated apoptotic signaling pathway 3 Target ID: GO:0036462 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23390247	Activator 1447
D2-like dopamine receptor 9 Target ID: CHEMBL2331075 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27602582	Antagonist 2849
Serine/threonine-protein kinase AKT 31 Target ID: CHEMBL4282 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23390247	Inhibitor 8504
Mitogen-activated protein kinase; ERK1/ERK2 4 Target ID: CHEMBL1907606 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23390247	Inhibitor 8504

Conditions

Condition	Modality	Highest Phase	Product
Glioblastoma 66 Sources: http://adisinsight.springer.com/drugs/800039735	Primary	Phase II 1147	Unknown Approved Use Unknown
Leukemia 72 Sources: http://adisinsight.springer.com/drugs/800039735	Primary	Phase II 1147	Unknown Approved Use Unknown
Non-Hodgkin's lymphoma 81 Sources: http://adisinsight.springer.com/drugs/800039735	Primary	Phase II 1147	Unknown Approved Use Unknown
Multiple myeloma 159 Sources: http://adisinsight.springer.com/drugs/800039735	Primary	Phase II 1147	Unknown Approved Use Unknown
Solid tumors 147 Sources: http://adisinsight.springer.com/drugs/800039735	Primary	Phase I 438	Unknown Approved Use Unknown
Lymphoma 60 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25587031	Primary	Preclinical	Unknown Approved Use Unknown
Colon cancer 66 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25587031	Primary	Preclinical	Unknown Approved Use Unknown
Triple-negative breast cancer 14 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 1946 inhibitor 2252	substrate 1193 inhibitor 2438	substrate 1388 inhibitor 2507

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
BCRP 910 CYP2B6 926 CYP2C8 1057 CYP2C19 2057 P-gp 1741	CYP2B6 776 CYP2C8 810 CYP2C19 1119	CYPs 17

Drug as perpetrator

Target	Modality	Activity
CYPs 35	inducer 1966 Sources: https://cancerres.aacrjournals.org/content/81/13_Supplement/1370.short	no
CYP2D6 2546	inhibitor 4027 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 2633	inhibitor 4027 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 1932	inhibitor 4027 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 2497	inhibitor 4027 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 985	inhibitor 4027 Sources: https://cancerres.aacrjournals.org/content/81/13_Supplement/1370.short	yes
CYP2B6 1160	inhibitor 4027 Sources: https://cancerres.aacrjournals.org/content/81/13_Supplement/1370.short	yes
CYP2C19 2141	inhibitor 4027 Sources: https://cancerres.aacrjournals.org/content/81/13_Supplement/1370.short	yes
CYP2C8 1117	inhibitor 4027 Sources: https://cancerres.aacrjournals.org/content/81/13_Supplement/1370.short	yes

Drug as victim

Target	Modality	Activity
CYP2B6 776	substrate 4014 Sources: https://cancerres.aacrjournals.org/content/81/13_Supplement/1370.short	yes
CYP2C19 1119	substrate 4014 Sources: https://cancerres.aacrjournals.org/content/81/13_Supplement/1370.short	yes
CYP2C8 810	substrate 4014 Sources: https://cancerres.aacrjournals.org/content/81/13_Supplement/1370.short	yes
CYP2C9 1193	substrate 4014 Sources: https://cancerres.aacrjournals.org/content/81/13_Supplement/1370.short	yes
CYP2D6 1388	substrate 4014 Sources: https://cancerres.aacrjournals.org/content/81/13_Supplement/1370.short	yes
CYP3A4 1946	substrate 4014 Sources: https://cancerres.aacrjournals.org/content/81/13_Supplement/1370.short	yes

PubMed

Title	Date	PubMed
Discovery and clinical introduction of first-in-class imipridone ONC201.	2016-11-08	27602582
mTOR inhibition sensitizes ONC201-induced anti-colorectal cancer cell activity.	2016-09-30	27565731
The preclinical evaluation of TIC10/ONC201 as an anti-pancreatic cancer agent.	2016-08-05	27233611
ONC201 kills solid tumor cells by triggering an integrated stress response dependent on ATF4 activation by specific eIF2α kinases.	2016-02-16	26884600
ATF4 induction through an atypical integrated stress response to ONC201 triggers p53-independent apoptosis in hematological malignancies.	2016-02-16	26884599
ONC201: Stressing tumors to death.	2016-02-16	26884598
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.	2015-11-03	26474387
ONC201 induces cell death in pediatric non-Hodgkin's lymphoma cells.	2015-08-03	26030065
Identification of TRAIL-inducing compounds highlights small molecule ONC201/TIC10 as a unique anti-cancer agent that activates the TRAIL pathway.	2015-05-01	25927855
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.	2015-04-15	25681273
Small-Molecule ONC201/TIC10 Targets Chemotherapy-Resistant Colorectal Cancer Stem-like Cells in an Akt/Foxo3a/TRAIL-Dependent Manner.	2015-04-01	25712124
TIC10/ONC201: a bend in the road to clinical development.	2015	25859547
The angular structure of ONC201, a TRAIL pathway-inducing compound, determines its potent anti-cancer activity.	2014-12-30	25587031
Pharmacophore reassignment for induction of the immunosurveillance cytokine TRAIL.	2014-06-23	24838721
Dual inactivation of Akt and ERK by TIC10 signals Foxo3a nuclear translocation, TRAIL gene induction, and potent antitumor effects.	2013-02-06	23390247

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 `Wed Apr 02 19:46:13 GMT 2025` Edited by `admin` on `Wed Apr 02 19:46:13 GMT 2025`
Record UNII	9U35A31JAI
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

ONC201

Preferred Name

English

Dordaviprone

Official Name

English

TIC-10

Code

English

dordaviprone [INN]

Common Name

English

7-benzyl-4-[(2-methylphenyl)methyl]-2,4,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(1H)-one

Systematic 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

DORDAVIPRONE [USAN]

Common Name

English

ONC 201 [WHO-DD]

Common Name

English

ONC-201

Code

English

NSC-350625

Code

English

Classification Tree Code System Code

FDA ORPHAN DRUG

553316