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dordaviprone   Click here for help

GtoPdb Ligand ID: 9978

Synonyms: Modeyso® | ONC-201 | ONC201 | TIC-10 | TIC10
Approved drug Immunopharmacology Ligand
dordaviprone is an approved drug
Compound class: Synthetic organic
Comment: Dordaviprone (ONC201, also known as TIC10 [2]) was originally discovered as a TRAIL pathway inducer and as an orally active dual Akt/ERK inhibitor [1]. It exerts potent anti-tumour effects [6,10-11].

ONC201 was later reported as an allosteric activator of the oncology drug target, mitochondrial protease caseinolytic protease P (ClpP) [4-5,9]. It also antagonises dopamine D2/3 receptor signalling [7-8].
2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/). All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 3
Hydrogen bond donors 0
Rotatable bonds 4
Topological polar surface area 42.53
Molecular weight 386.21
XLogP 5.24
No. Lipinski's rules broken 1

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)

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Canonical SMILES Cc1ccccc1Cn1c(=O)c2CN(CCc2n2c1=NCC2)Cc1ccccc1
Isomeric SMILES Cc1ccccc1Cn1c(=O)c2CN(CCc2n2c1=NCC2)Cc1ccccc1
InChI 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
InChI Key VLULRUCCHYVXOH-UHFFFAOYSA-N

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
References
1. Allen JE, Kline CL, Prabhu VV, Wagner J, Ishizawa J, Madhukar N, Lev A, Baumeister M, Zhou L, Lulla A et al.. (2016)
Discovery and clinical introduction of first-in-class imipridone ONC201.
Oncotarget, 7 (45): 74380-74392. [PMID:27602582]
2. Allen JE, Krigsfeld G, Mayes PA, Patel L, Dicker DT, Patel AS, Dolloff NG, Messaris E, Scata KA, Wang W et al.. (2013)
Dual inactivation of Akt and ERK by TIC10 signals Foxo3a nuclear translocation, TRAIL gene induction, and potent antitumor effects.
Sci Transl Med, 5 (171): 171ra17. [PMID:23390247]
3. Arrillaga-Romany I, Lassman A, McGovern SL, Mueller S, Nabors B, van den Bent M, Vogelbaum MA, Allen JE, Melemed AS, Tarapore RS et al.. (2024)
ACTION: a randomized phase 3 study of ONC201 (dordaviprone) in patients with newly diagnosed H3 K27M-mutant diffuse glioma.
Neuro Oncol, 26 (Supplement_2): S173-S181. [PMID:38445964]
4. Goncalves MM, Uday AB, Forrester TJB, Currie SQW, Kim AS, Feng Y, Jitkova Y, Velyvis A, Harkness RW, Kimber MS et al.. (2025)
Mechanism of allosteric activation in human mitochondrial ClpP protease.
Proc Natl Acad Sci U S A, 122 (16): e2419881122. [PMID:40232800]
5. Ishizawa J, Zarabi SF, Davis RE, Halgas O, Nii T, Jitkova Y, Zhao R, St-Germain J, Heese LE, Egan G et al.. (2019)
Mitochondrial ClpP-Mediated Proteolysis Induces Selective Cancer Cell Lethality.
Cancer Cell, 35 (5): 721-737.e9. [PMID:31056398]
6. Karpel-Massler G, Bâ M, Shu C, Halatsch ME, Westhoff MA, Bruce JN, Canoll P, Siegelin MD. (2015)
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.
Oncotarget, 6 (34): 36456-71. [PMID:26474387]
7. Kline CLB, Ralff MD, Lulla AR, Wagner JM, Abbosh PH, Dicker DT, Allen JE, El-Deiry WS. (2018)
Role of Dopamine Receptors in the Anticancer Activity of ONC201.
Neoplasia, 20 (1): 80-91. [PMID:29216597]
8. Madhukar NS, Elemento O, Benes CH, Garnett MJ, Stein M, Bertino JR, Kaufman HL, Arrillaga-Romany I, Batchelor TT, Schalop L et al.. (2016)
Abstract LB-209: D2-like dopamine receptor antagonism by ONC201 identified by confluence of computational, receptor binding, and clinical studies.
Cancer Research, 76 (14_Supplement): LB-209. DOI: 10.1158/1538-7445.AM2016-LB-209
9. Prabhu VV, Morrow S, Rahman Kawakibi A, Zhou L, Ralff M, Ray J, Jhaveri A, Ferrarini I, Lee Y, Parker C et al.. (2020)
ONC201 and imipridones: Anti-cancer compounds with clinical efficacy.
Neoplasia, 22 (12): 725-744. [PMID:33142238]
10. Talekar MK, Allen JE, Dicker DT, El-Deiry WS. (2015)
ONC201 induces cell death in pediatric non-Hodgkin's lymphoma cells.
Cell Cycle, 14 (15): 2422-8. [PMID:26030065]
11. Wagner J, Kline CL, Pottorf RS, Nallaganchu BR, Olson GL, Dicker DT, Allen JE, El-Deiry WS. (2014)
The angular structure of ONC201, a TRAIL pathway-inducing compound, determines its potent anti-cancer activity.
Oncotarget, 5 (24): 12728-37. [PMID:25587031]
12. Wagner J, Kline CL, Zhou L, Campbell KS, MacFarlane AW, Olszanski AJ, Cai KQ, Hensley HH, Ross EA, Ralff MD et al.. (2018)
Dose intensification of TRAIL-inducing ONC201 inhibits metastasis and promotes intratumoral NK cell recruitment.
J Clin Invest, 128 (6): 2325-2338. [PMID:29533922]