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Dordaviprone (TIC10; imipridone, ONC201), an imipridone compound, is a novel, potent, orally bioavailable, brain/BBB penetrant, and stable tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) inducer with potential anticancer activity. It was initially developed in the 1970s as an anti-seizure agent which acts by inhibiting Akt and ERK, consequently activating Foxo3a and significantly inducing cell surface TRAIL. TIC10 can inactivate Akt and ERK to induce TRAIL through Foxo3a, possesses superior drug properties: delivery across the blood-brain barrier, superior stability and improved pharmacokinetics. TIC10 is a potent, orally active, and stable small molecule that transcriptionally induces TRAIL in a p53-independent manner. TIC10 induces a sustained up-regulation of TRAIL in tumors and normal cells that may contribute to the demonstrable antitumor activity of TIC10.
On August 6, 2025, the Food and Drug Administration granted accelerated approval to dordaviprone (Modeyso, Jazz Pharmaceuticals, Inc.), a protease activator, for adult and pediatric patients 1 year of age and older with diffuse midline glioma harboring an H3 K27M mutation with progressive disease following prior therapy. This represents the first FDA approval of a systemic therapy for H3 K27M-mutant diffuse midline glioma.Physicochemical Properties
| Molecular Formula | C24H26N4O | |
| Molecular Weight | 386.49 | |
| Exact Mass | 386.21 | |
| Elemental Analysis | C, 74.58; H, 6.78; N, 14.50; O, 4.14 | |
| CAS # | 1616632-77-9 | |
| Related CAS # | 41276-02-2 (isomer);1616632-77-9;1638178-82-1 (HCl);1777785-71-3 (HBr);2007141-57-1 (2HBr); | |
| PubChem CID | 73777259 | |
| Appearance | White to off-white solid powder | |
| Density | 1.2±0.1 g/cm3 | |
| Boiling Point | 559.7±60.0 °C at 760 mmHg | |
| Flash Point | 292.3±32.9 °C | |
| Vapour Pressure | 0.0±1.5 mmHg at 25°C | |
| Index of Refraction | 1.672 | |
| LogP | 3.14 | |
| Hydrogen Bond Donor Count | 0 | |
| Hydrogen Bond Acceptor Count | 3 | |
| Rotatable Bond Count | 4 | |
| Heavy Atom Count | 29 | |
| Complexity | 693 | |
| Defined Atom Stereocenter Count | 0 | |
| SMILES | O=C1C2C([H])([H])N(C([H])([H])C3C([H])=C([H])C([H])=C([H])C=3[H])C([H])([H])C([H])([H])C=2N2C([H])([H])C([H])([H])N=C2N1C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1C([H])([H])[H] |
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| InChi Key | RSAQARAFWMUYLL-UHFFFAOYSA-N | |
| InChi Code | InChI=1S/C24H26N4O/c1-18-7-5-6-10-20(18)16-28-22-11-13-26(15-19-8-3-2-4-9-19)17-21(22)23(29)27-14-12-25-24(27)28/h2-10H,11-17H2,1H3 | |
| Chemical Name | 7-benzyl-4-(2-methylbenzyl)-1,2,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(4H)-one | |
| Synonyms |
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| HS Tariff Code | 2934.99.9001 | |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | Akt; ERK |
| ln Vitro | In several cancer cell lines, TIC10 induces TRAIL protein localization on the cell surface in a p53-independent manner and increases TRAIL mRNA in a dose-dependent manner. While TIC10 exhibits broad-spectrum anti-tumor activity in vitro and causes TRAIL-sensitive HCT116 p53/p53 cells to exhibit an increase in sub-G1 DNA content indicative of cell death, normal fibroblasts are unaffected by TIC10 at equivalent doses. TIC10 spares healthy fibroblasts while reducing the clonogenic survival of cancer cell lines. Similar to TRAIL-mediated apoptosis, TIC10 increases the proportion of sub-G1 DNA in cancer cells in a p53-independent and Bax-dependent manner. The up-regulation of TRAIL caused by TIC10 is dependent on Foxo3a, which also up-regulates the TRAIL death receptor DR5 and other targets, possibly making some TRAIL-resistant tumor cells susceptible. ERK and Akt kinases are inactivated by TIC10, which causes Foxo3a to move into the nucleus and bind to the TRAIL promoter to activate gene transcription. Foxo3a is then transported into the nucleus. The effective antitumor drug TIC10 works by increasing the levels of the naturally occurring tumor suppressor TRAIL in tumor cells and their surrounding tissue. [1] |
| ln Vivo | TIC10 and TRAIL treatment causes tumor regression in the HCT116 p53−/− xenograft to a comparable extent when both are administered as multiple doses. TIC10 also induces regression of MDA-MB-231 human triple-negative breast cancer xenografts, whereas TRAIL-treated tumors progressed. In DLD-1 colon cancer xenografts, TIC10 induces tumor stasis one week after treatment, whereas TRAIL-treated tumors advance after a single dose. The SW480 xenograft also exhibits a sustained regression after receiving a single dose of TIC10, and this effect is seen whether the drug is administered orally or intraperitoneally. This suggests that TIC10 has a favorable oral bioavailability. TIC10 causes tumor-specific cell death by TRAIL-mediated direct and bystander effects. TIC10 is an effective antitumor agent against orthotopic human glioblastoma multiforme tumors. [1] |
| Enzyme Assay |
ChIP assays [1] ChIP assays were carried out as previously described for the TRAIL promoter with a ChIP-grade antibody for Foxo3a or an equivalent concentration of rabbit immunoglobulin G as a nonspecific control. |
| Cell Assay |
Cells were treated with 10 μM ONC201 or DMSO for 24 h. Colony formation assays [1] The indicated cell lines were plated at 500 cells per well and allowed to adhere, and then treated the next day in fresh complete medium. At 3 days after treatment, the medium was replaced with drug-free medium and cells were propagated for 10 days, with fresh medium given once every 3 days. At the end of the 10-day period, cells were washed in PBS, fixed with methanol, stained with Coomassie blue, rinsed, and dried for quantification. Western blot analysis [1] Western blot analysis was conducted as previously described (41) with NuPAGE 4 to 12% bis-tris gel and visualized with SuperSignal West Femto and x-ray film. Densitometry was performed with NIH ImageJ. Nuclear and cytoplasmic extracts were prepared with a cytoplasmic lysis buffer (10 mM Hepes, 10 mM KCl, 2 mM MgCl2, 1 mM dithiothreitol) followed by a nuclear lysis buffer (20 mM Hepes, 420 mM NaCl, 1.5 mM MgCl2, 250 μM EDTA, 25% glycerol). For all lysis buffers, fresh protease inhibitor and 1 mM sodium orthovanadate were added immediately before use. |
| Animal Protocol |
Female athymic nu/nu mice 25, 50, 100 mg/kg Intraperitoneal/oral All animal experiments were conducted in accordance with the Institutional Animal Care and Use Committee at the Pennsylvania State University College of Medicine. For subcutaneous xenografts, 4- to 6-week-old female athymic nu/nu mice (Charles River Laboratories) were inoculated with 1 × 106 cells (2.5 × 106 for T98G) of the indicated cell lines in each rear flank as a 200-μl suspension of 1:1 Matrigel (BD)/PBS. All subcutaneous tumors were allowed to establish for 1 to 4 weeks after injection until reaching a volume of ~125 mm3 before treatment initiation.[1] |
| ADME/Pharmacokinetics |
Absorption Dordaviprone maximum concentration (Cmax) is 2.8 mcg/mL (42%), and total systemic exposure (AUC) is 23 hr x mcg/mL (48%). Dordaviprone Cmax and AUC increased in a dose proportional manner over the dose range of 125 to 625 mg. Dordaviprone median (min, max) time to maximum plasma concentration (Tmax) is 1.4 hours (0.5, 5.6 hours). Dordaviprone Cmax decreased by 40% with no change on AUC following administration with a high-fat meal (800 to 1,000 calories, 50% fat). Route of Elimination Following a single dose of radiolabeled dordaviprone, about 70% of the dose was recovered in urine and 20% in feces with no notable unchanged dordaviprone in urine or feces. Volume of Distribution Dordaviprone apparent (oral) volume of distribution is 450 L (40%). The median blood-to-plasma ratio is 0.67 in vitro. Dordaviprone crosses the blood-brain barrier. Clearance The apparent clearance is approximately 27 L/hr (48%). Protein Binding Dordaviprone plasma protein binding is 95% to 97% and independent of concentrations in vitro. Metabolism / Metabolites Dordaviprone is primarily metabolized by CYP3A4 with minor contribution from CYP2B6, CYP2C8, CYP2C9, CYP2D6, and CYP3A5. The metabolic pathways and the metabolites have not been fully characterized. Biological Half-Life Dordaviprone mean terminal half-life is 11 hours (30%). |
| Toxicity/Toxicokinetics | Efficacy and Safety Efficacy was evaluated in an integrated efficacy population of 50 adult and pediatric patients with recurrent H3 K27M-mutant diffuse midline glioma enrolled across five open-label, non-randomized clinical trials conducted in the U.S. (ONC006 [NCT02525692], ONC013 [NCT03295396], ONC014 [NCT03416530], ONC016 [NCT05392374], and ONC018 [NCT03134131]). The efficacy population comprised patients who received single-agent dordaviprone for diffuse midline glioma harboring an H3 K27M mutation and had progressive and measurable disease per Response Assessment in Neuro-Oncology-High Grade Glioma (RANO-HGG) criteria. Patients were also at least 90 days post radiation therapy, had an adequate washout period from prior anticancer therapies, a Karnofsky Performance Status/Lansky Performance Status (KPS/LPS) score ≥60, and stable or decreasing corticosteroid use. Patients with diffuse intrinsic pontine glioma, primary spinal tumors, atypical histologies, or cerebrospinal fluid dissemination were excluded. The major efficacy outcome measure was overall response rate (ORR) assessed by blinded independent central review (BICR) according to RANO 2.0 criteria, with duration of response (DOR) as a secondary outcome measure. ORR was 22% (95% CI: 12, 36) and median DOR was 10.3 months (95% CI: 7.3, 15.2). Among the 11 patients with objective responses, 73% had a DOR of ≥ 6 months and 27% had a DOR of ≥ 12 months. The dordaviprone prescribing information includes warnings and precautions for hypersensitivity, QTc interval prolongation, and embryo-fetal toxicity. |
| References |
[1]. Sci Transl Med. 2013 Feb 6;5(171):171ra17. [2]. ACS Chem Biol. 2019 May 17;14(5):1020-1029. |
| Additional Infomation |
Dordaviprone (ONC-201) is under investigation in clinical trial NCT03394027 (ONC201 in Recurrent/Refractory Metastatic Breast Cancer and Advanced Endometrial Carcinoma). Dordaviprone is a water soluble, orally bioavailable inhibitor of the serine/threonine protein kinase Akt (protein kinase B) and extracellular signal-regulated kinase (ERK), with potential antineoplastic activity. Upon administration, dordaviprone binds to and inhibits the activity of Akt and ERK, which may result in inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt signal transduction pathway as well as the mitogen-activated protein kinase (MAPK)/ERK-mediated pathway. This may lead to the induction of tumor cell apoptosis mediated by tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)/TRAIL death receptor type 5 (DR5) signaling in AKT/ERK-overexpressing tumor cells. The PI3K/Akt signaling pathway and MAPK/ERK pathway are upregulated in a variety of tumor cell types and play a key role in tumor cell proliferation, differentiation and survival by inhibiting apoptosis. In addition, ONC201 is able to cross the blood-brain barrier. Recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an antitumor protein that is in clinical trials as a potential anticancer therapy but suffers from drug properties that may limit efficacy such as short serum half-life, stability, cost, and biodistribution, particularly with respect to the brain. To overcome such limitations, we identified TRAIL-inducing compound 10 (TIC10), a potent, orally active, and stable small molecule that transcriptionally induces TRAIL in a p53-independent manner and crosses the blood-brain barrier. TIC10 induces a sustained up-regulation of TRAIL in tumors and normal cells that may contribute to the demonstrable antitumor activity of TIC10. 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 is an efficacious antitumor therapeutic agent that acts on tumor cells and their microenvironment to enhance the concentrations of the endogenous tumor suppressor TRAIL. [1] ONC201 is a first-in-class imipridone molecule currently in clinical trials for the treatment of multiple cancers. Despite enormous clinical potential, the mechanism of action is controversial. To investigate the mechanism of ONC201 and identify compounds with improved potency, we tested a series of novel ONC201 analogues (TR compounds) for effects on cell viability and stress responses in breast and other cancer models. The TR compounds were found to be ∼50-100 times more potent at inhibiting cell proliferation and inducing the integrated stress response protein ATF4 than ONC201. Using immobilized TR compounds, we identified the human mitochondrial caseinolytic protease P (ClpP) as a specific binding protein by mass spectrometry. Affinity chromatography/drug competition assays showed that the TR compounds bound ClpP with ∼10-fold higher affinity compared to ONC201. Importantly, we found that the peptidase activity of recombinant ClpP was strongly activated by ONC201 and the TR compounds in a dose- and time-dependent manner with the TR compounds displaying a ∼10-100 fold increase in potency over ONC201. Finally, siRNA knockdown of ClpP in SUM159 cells reduced the response to ONC201 and the TR compounds, including induction of CHOP, loss of the mitochondrial proteins (TFAM, TUFM), and the cytostatic effects of these compounds. Thus, we report that ClpP directly binds ONC201 and the related TR compounds and is an important biological target for this class of molecules. Moreover, these studies provide, for the first time, a biochemical basis for the difference in efficacy between ONC201 and the TR compounds. [2] Pharmacodynamics: Dordaviprone is a drug with anti-tumour activity: It exhibited anti-tumour activity in cell-based assays and in vivo models of H3 K27M-mutant diffuse glioma. Dordaviprone causes a concentration-dependent QTc interval prolongation. At 1.2 times the maximum recommended dose, the estimated mean QTcF change was 11.8 msec (90% CI: 9.8, 13.7). The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of dordaviprone have not been fully characterized. Mechanism of Action: Dordaviprone is a protease activator of the mitochondrial caseinolytic protease P (ClpP), a mitochondrial serine protease. Diffuse midline gliomas harboring an H3 K27M mutation are associated with the loss of H3 K27 trimethylation. In vitro, dordaviprone induced apoptosis and altered mitochondrial metabolism leading to restored histone H3 K27 trimethylation in H3 K27M-mutant diffuse glioma models. Dordaviprone activates ATF4 and induces endoplasmic reticulum (ER) stress response or integrated stress response (ISR). Dordaviprone also inhibits the dopamine D2 receptor, which are often overexpressed in multiple cancers, including glioblastoma. |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples. Injection Formulations (e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] *Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline) Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline) Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline) Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil) Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Oral Formulations Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). Oral Formulation 3: Dissolved in PEG400 Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose Oral Formulation 6: Mixing with food powders Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5874 mL | 12.9369 mL | 25.8739 mL | |
| 5 mM | 0.5175 mL | 2.5874 mL | 5.1748 mL | |
| 10 mM | 0.2587 mL | 1.2937 mL | 2.5874 mL |