Dordaviprone

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

Description
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).

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 1430
TRAIL-activated apoptotic signaling pathway 3 Target ID: GO:0036462 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23390247	Activator 1430
D2-like dopamine receptor 9 Target ID: CHEMBL2331075 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27602582	Antagonist 2778

Conditions

Condition	Modality	Highest Phase	Product
Glioblastoma 65 Sources: http://adisinsight.springer.com/drugs/800039735	Primary	Phase II 1132	Unknown Approved Use Unknown
Leukemia 87 Sources: http://adisinsight.springer.com/drugs/800039735	Primary	Phase II 1132	Unknown Approved Use Unknown
Non-Hodgkin's lymphoma 79 Sources: http://adisinsight.springer.com/drugs/800039735	Primary	Phase II 1132	Unknown Approved Use Unknown
Multiple myeloma 159 Sources: http://adisinsight.springer.com/drugs/800039735	Primary	Phase II 1132	Unknown Approved Use Unknown
Solid tumors 145 Sources: http://adisinsight.springer.com/drugs/800039735	Primary	Phase I 428	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 1737 inhibitor 1587	substrate 1037 inhibitor 1767	substrate 1217 inhibitor 1852

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
BCRP 699 CYP2B6 810 CYP2C8 911 CYP2C19 1478 P-gp 1461	Efflux transporters 3 CYP2B6 664 CYP2C8 693 CYP2C19 991	CYPs 12

Drug as perpetrator

Target	Modality	Activity
CYPs 28	inducer 1573 Sources: https://cancerres.aacrjournals.org/content/81/13_Supplement/1370.short	no
CYP2D6 1891	inhibitor 3277 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 1925	inhibitor 3277 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 1650	inhibitor 3277 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 1819	inhibitor 3277 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 773	inhibitor 3277 Sources: https://cancerres.aacrjournals.org/content/81/13_Supplement/1370.short	yes
CYP2B6 1001	inhibitor 3277 Sources: https://cancerres.aacrjournals.org/content/81/13_Supplement/1370.short	yes
CYP2C19 1553	inhibitor 3277 Sources: https://cancerres.aacrjournals.org/content/81/13_Supplement/1370.short	yes
CYP2C8 965	inhibitor 3277 Sources: https://cancerres.aacrjournals.org/content/81/13_Supplement/1370.short	yes

Drug as victim

Target	Modality	Activity
Efflux transporters 3	substrate 3367 Sources: https://cancerres.aacrjournals.org/content/81/13_Supplement/1370.short	no
CYP2B6 664	substrate 3367 Sources: https://cancerres.aacrjournals.org/content/81/13_Supplement/1370.short	yes
CYP2C19 991	substrate 3367 Sources: https://cancerres.aacrjournals.org/content/81/13_Supplement/1370.short	yes
CYP2C8 693	substrate 3367 Sources: https://cancerres.aacrjournals.org/content/81/13_Supplement/1370.short	yes
CYP2C9 1037	substrate 3367 Sources: https://cancerres.aacrjournals.org/content/81/13_Supplement/1370.short	yes
CYP2D6 1217	substrate 3367 Sources: https://cancerres.aacrjournals.org/content/81/13_Supplement/1370.short	yes
CYP3A4 1737	substrate 3367 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
The angular structure of ONC201, a TRAIL pathway-inducing compound, determines its potent anti-cancer activity.	2014 Dec 30	25587031
Pharmacophore reassignment for induction of the immunosurveillance cytokine TRAIL.	2014 Jun 23	24838721
TIC10/ONC201: a bend in the road to clinical development.	2015	25859547
Small-Molecule ONC201/TIC10 Targets Chemotherapy-Resistant Colorectal Cancer Stem-like Cells in an Akt/Foxo3a/TRAIL-Dependent Manner.	2015 Apr 1	25712124
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	25681273
ONC201 induces cell death in pediatric non-Hodgkin's lymphoma cells.	2015 Aug 3	26030065
Identification of TRAIL-inducing compounds highlights small molecule ONC201/TIC10 as a unique anti-cancer agent that activates the TRAIL pathway.	2015 May 1	25927855
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
The preclinical evaluation of TIC10/ONC201 as an anti-pancreatic cancer agent.	2016 Aug 5	27233611
ONC201 kills solid tumor cells by triggering an integrated stress response dependent on ATF4 activation by specific eIF2α kinases.	2016 Feb 16	26884600
ATF4 induction through an atypical integrated stress response to ONC201 triggers p53-independent apoptosis in hematological malignancies.	2016 Feb 16	26884599
ONC201: Stressing tumors to death.	2016 Feb 16	26884598
Discovery and clinical introduction of first-in-class imipridone ONC201.	2016 Nov 8	27602582
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.

Name

Type

Language

Dordaviprone

Official Name

English

ONC201

Code

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