ONC-201 (TIC-10)
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MedKoo CAT#: 206124

CAS#: 1616632-77-9 (free base)

Description: ONC-201, also known as TIC10 and imipridone, is 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.


Chemical Structure

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ONC-201 (TIC-10)
CAS# 1616632-77-9 (free base)

Theoretical Analysis

MedKoo Cat#: 206124
Name: ONC-201 (TIC-10)
CAS#: 1616632-77-9 (free base)
Chemical Formula: C24H26N4O
Exact Mass: 386.21066
Molecular Weight: 386.49
Elemental Analysis: C, 74.58; H, 6.78; N, 14.50; O, 4.14

Price and Availability

Size Price Availability Quantity
50.0mg USD 90.0 Ready to ship
100.0mg USD 150.0 Ready to ship
200.0mg USD 250.0 Ready to ship
500.0mg USD 550.0 Ready to ship
1.0g USD 950.0 Ready to ship
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Related CAS #: 41276-02-2 (TIC10 isomer)   1616632-77-9 (free base)   1638178-82-1 (HCl)   1777785-71-3 (HBr)   2007141-57-1 (2HBr)    

Synonym: ONC201; ONC 201; ONC-201; NSC350625; NSC-350625; NSC 350625; TIC10; TIC 10; TIC-10; TRAIL inducing compound 10; imipridone

IUPAC/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

InChi Key: VLULRUCCHYVXOH-UHFFFAOYSA-N

InChi Code: 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

SMILES Code: O=C1N(CC2=CC=CC=C2C)C3=NCCN3C4=C1CN(CC5=CC=CC=C5)CC4

Appearance: White to off-white solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not soluble in water

Shelf Life: >2 years if stored properly

Drug Formulation: TIC10 is not water soluble, may be dissolved in DMSO, then is formulated in 20% Cremophor EL, 10% DMSO, and 70% PBS buffer.

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: TRAIL inducer which acts by inhibiting Akt and ERK
In vitro activity: The treatment of PC3 cells, a cell line known to be radiation-resistant34, with ONC201 (5, 10 and 15 µM35) significantly induced cell death at 72 h (Fig. 1a). Interestingly, the cytotoxic effect observed with ONC201 at 72 h occurred after an early increase in the expression of all the main components of the UPR at 24 h (Fig. 1b; Supplementary Fig. 11a). This occurred despite any significant inhibition of Akt phosphorylation and despite the fact that PC3 cells express very low levels of DRD2, a reported molecular target of ONC201 (Supplementary Fig. 10b,c—associated full-length blots in Supplementary Fig. 12). Reference: Sci Rep. 2021; 11: 4252. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896060/
In vivo activity: ONC201 administration was found to significantly decrease p24-positive cells as a percentage to total CD68-positive cells (Fig. 4J), compared with those in the vehicle control group. These data suggest that ONC201 reduces the number of HIV-1-infected macrophages in the in vivo NSG mouse model. In order to better quantitatively determine the levels of HIV-1 inhibition, tissues that contained injection sites were homoegnized and subjected the tissue lysates to Western blots (Fig. 4K). The quantification data revealed that p24 levels significantly decreased in the ONC201 group compared with the control group (Fig. 4L). In contrast, CD68 levels were comparable in all of the brain lysates. As a result, the ratio of p24 to CD68 significantly decreased after ONC201 treatment (Fig. 4M), which is consistent with the p24 and CD68 staining data. Together, these data in HIV-1-infected NSG mice demonstrate that ONC201 is able to inhibit HIV-1 replication in macrophages in vivo. Reference: Antiviral Res. 2019 Aug; 168: 134–145. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620139/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 30.0 77.6

Preparing Stock Solutions

The following data is based on the product molecular weight 386.49 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Amoroso F, Glass K, Singh R, Liberal F, Steele RE, Maguire S, Tarapore R, Allen JE, Van Schaeybroeck S, Butterworth KT, Prise K, O'Sullivan JM, Jain S, Waugh DJ, Mills IG. Modulating the unfolded protein response with ONC201 to impact on radiation response in prostate cancer cells. Sci Rep. 2021 Feb 19;11(1):4252. doi: 10.1038/s41598-021-83215-y. PMID: 33608585; PMCID: PMC7896060. 2. Ralff MD, Jhaveri A, Ray JE, Zhou L, Lev A, Campbell KS, Dicker DT, Ross EA, El-Deiry WS. TRAIL receptor agonists convert the response of breast cancer cells to ONC201 from anti-proliferative to apoptotic. Oncotarget. 2020 Oct 20;11(42):3753-3769. doi: 10.18632/oncotarget.27773. PMID: 33144917; PMCID: PMC7584235. 3. Zhao R, Li Y, Gorantla S, Poluektova LY, Lin H, Gao F, Wang H, Zhao J, Zheng JC, Huang Y. Small molecule ONC201 inhibits HIV-1 replication in macrophages via FOXO3a and TRAIL. Antiviral Res. 2019 Aug;168:134-145. doi: 10.1016/j.antiviral.2019.05.015. Epub 2019 May 31. PMID: 31158413; PMCID: PMC6620139. 4. Hayes-Jordan AA, Ma X, Menegaz BA, Lamhamedi-Cherradi SE, Kingsley CV, Benson JA, Camacho PE, Ludwig JA, Lockworth CR, Garcia GE, Craig SL. Efficacy of ONC201 in Desmoplastic Small Round Cell Tumor. Neoplasia. 2018 May;20(5):524-532. doi: 10.1016/j.neo.2018.02.006. Epub 2018 Apr 5. PMID: 29626752; PMCID: PMC5915995.
In vitro protocol: 1. Amoroso F, Glass K, Singh R, Liberal F, Steele RE, Maguire S, Tarapore R, Allen JE, Van Schaeybroeck S, Butterworth KT, Prise K, O'Sullivan JM, Jain S, Waugh DJ, Mills IG. Modulating the unfolded protein response with ONC201 to impact on radiation response in prostate cancer cells. Sci Rep. 2021 Feb 19;11(1):4252. doi: 10.1038/s41598-021-83215-y. PMID: 33608585; PMCID: PMC7896060. 2. Ralff MD, Jhaveri A, Ray JE, Zhou L, Lev A, Campbell KS, Dicker DT, Ross EA, El-Deiry WS. TRAIL receptor agonists convert the response of breast cancer cells to ONC201 from anti-proliferative to apoptotic. Oncotarget. 2020 Oct 20;11(42):3753-3769. doi: 10.18632/oncotarget.27773. PMID: 33144917; PMCID: PMC7584235.
In vivo protocol: 1. Zhao R, Li Y, Gorantla S, Poluektova LY, Lin H, Gao F, Wang H, Zhao J, Zheng JC, Huang Y. Small molecule ONC201 inhibits HIV-1 replication in macrophages via FOXO3a and TRAIL. Antiviral Res. 2019 Aug;168:134-145. doi: 10.1016/j.antiviral.2019.05.015. Epub 2019 May 31. PMID: 31158413; PMCID: PMC6620139. 2. Hayes-Jordan AA, Ma X, Menegaz BA, Lamhamedi-Cherradi SE, Kingsley CV, Benson JA, Camacho PE, Ludwig JA, Lockworth CR, Garcia GE, Craig SL. Efficacy of ONC201 in Desmoplastic Small Round Cell Tumor. Neoplasia. 2018 May;20(5):524-532. doi: 10.1016/j.neo.2018.02.006. Epub 2018 Apr 5. PMID: 29626752; PMCID: PMC5915995.

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1: Pruss M, Dwucet A, Tanriover M, Hlavac M, Kast RE, Debatin KM, Wirtz CR, Halatsch ME, Siegelin MD, Westhoff MA, Karpel-Massler G. Dual metabolic reprogramming by ONC201/TIC10 and 2-Deoxyglucose induces energy depletion and synergistic anti-cancer activity in glioblastoma. Br J Cancer. 2020 Apr;122(8):1146-1157. doi: 10.1038/s41416-020-0759-0. Epub 2020 Mar 2. PMID: 32115576; PMCID: PMC7156767.

2: Jacques S, van der Sloot AM, C Huard C, Coulombe-Huntington J, Tsao S, Tollis S, Bertomeu T, Culp EJ, Pallant D, Cook MA, Bonneil E, Thibault P, Wright GD, Tyers M. Imipridone Anticancer Compounds Ectopically Activate the ClpP Protease and Represent a New Scaffold for Antibiotic Development. Genetics. 2020 Apr;214(4):1103-1120. doi: 10.1534/genetics.119.302851. Epub 2020 Feb 24. PMID: 32094149; PMCID: PMC7153937.

3: Dianat-Moghadam H, Heidarifard M, Mahari A, Shahgolzari M, Keshavarz M, Nouri M, Amoozgar Z. TRAIL in oncology: From recombinant TRAIL to nano- and self- targeted TRAIL-based therapies. Pharmacol Res. 2020 May;155:104716. doi: 10.1016/j.phrs.2020.104716. Epub 2020 Feb 18. PMID: 32084560.

4: Wierzbicki K, Ravi K, Franson A, Bruzek A, Cantor E, Harris M, Homan MJ, Marini BL, Kawakibi AR, Ravindran R, Teodoro R, Yadav VN, Koschmann C. Targeting and Therapeutic Monitoring of H3K27M-Mutant Glioma. Curr Oncol Rep. 2020 Feb 6;22(2):19. doi: 10.1007/s11912-020-0877-0. Erratum in: Curr Oncol Rep. 2020 Apr 16;22(5):47. PMID: 32030483.

5: Madhukar NS, Khade PK, Huang L, Gayvert K, Galletti G, Stogniew M, Allen JE, Giannakakou P, Elemento O. A Bayesian machine learning approach for drug target identification using diverse data types. Nat Commun. 2019 Nov 19;10(1):5221. doi: 10.1038/s41467-019-12928-6. PMID: 31745082; PMCID: PMC6863850.

6: Arrillaga-Romany I, Odia Y, Prabhu VV, Tarapore RS, Merdinger K, Stogniew M, Oster W, Allen JE, Mehta M, Batchelor TT, Wen PY. Biological activity of weekly ONC201 in adult recurrent glioblastoma patients. Neuro Oncol. 2020 Jan 11;22(1):94-102. doi: 10.1093/neuonc/noz164. PMID: 31702782; PMCID: PMC7080220.

7: Chi AS, Tarapore RS, Hall MD, Shonka N, Gardner S, Umemura Y, Sumrall A, Khatib Z, Mueller S, Kline C, Zaky W, Khatua S, Weathers SP, Odia Y, Niazi TN, Daghistani D, Cherrick I, Korones D, Karajannis MA, Kong XT, Minturn J, Waanders A, Arillaga-Romany I, Batchelor T, Wen PY, Merdinger K, Schalop L, Stogniew M, Allen JE, Oster W, Mehta MP. Pediatric and adult H3 K27M-mutant diffuse midline glioma treated with the selective DRD2 antagonist ONC201. J Neurooncol. 2019 Oct;145(1):97-105. doi: 10.1007/s11060-019-03271-3. Epub 2019 Aug 27. PMID: 31456142.

8: Zhao R, Li Y, Gorantla S, Poluektova LY, Lin H, Gao F, Wang H, Zhao J, Zheng JC, Huang Y. Small molecule ONC201 inhibits HIV-1 replication in macrophages via FOXO3a and TRAIL. Antiviral Res. 2019 Aug;168:134-145. doi: 10.1016/j.antiviral.2019.05.015. Epub 2019 May 31. PMID: 31158413; PMCID: PMC6620139.

9: Cao Z, Liao Q, Su M, Huang K, Jin J, Cao D. AKT and ERK dual inhibitors: The way forward? Cancer Lett. 2019 Sep 10;459:30-40. doi: 10.1016/j.canlet.2019.05.025. Epub 2019 May 23. PMID: 31128213.

10: Nii T, Prabhu VV, Ruvolo V, Madhukar N, Zhao R, Mu H, Heese L, Nishida Y, Kojima K, Garnett MJ, McDermott U, Benes CH, Charter N, Deacon S, Elemento O, Allen JE, Oster W, Stogniew M, Ishizawa J, Andreeff M. Imipridone ONC212 activates orphan G protein-coupled receptor GPR132 and integrated stress response in acute myeloid leukemia. Leukemia. 2019 Dec;33(12):2805-2816. doi: 10.1038/s41375-019-0491-z. Epub 2019 May 24. PMID: 31127149; PMCID: PMC6874902.

11: Stein MN, Malhotra J, Tarapore RS, Malhotra U, Silk AW, Chan N, Rodriguez L, Aisner J, Aiken RD, Mayer T, Haffty BG, Newman JH, Aspromonte SM, Bommareddy PK, Estupinian R, Chesson CB, Sadimin ET, Li S, Medina DJ, Saunders T, Frankel M, Kareddula A, Damare S, Wesolowsky E, Gabel C, El-Deiry WS, Prabhu VV, Allen JE, Stogniew M, Oster W, Bertino JR, Libutti SK, Mehnert JM, Zloza A. Safety and enhanced immunostimulatory activity of the DRD2 antagonist ONC201 in advanced solid tumor patients with weekly oral administration. J Immunother Cancer. 2019 May 22;7(1):136. doi: 10.1186/s40425-019-0599-8. PMID: 31118108; PMCID: PMC6532211.

12: Wang S, Dougan DA. The Direct Molecular Target for Imipridone ONC201 Is Finally Established. Cancer Cell. 2019 May 13;35(5):707-708. doi: 10.1016/j.ccell.2019.04.010. PMID: 31085171.

13: Ishizawa J, Zarabi SF, Davis RE, Halgas O, Nii T, Jitkova Y, Zhao R, St- Germain J, Heese LE, Egan G, Ruvolo VR, Barghout SH, Nishida Y, Hurren R, Ma W, Gronda M, Link T, Wong K, Mabanglo M, Kojima K, Borthakur G, MacLean N, Ma MCJ, Leber AB, Minden MD, Houry W, Kantarjian H, Stogniew M, Raught B, Pai EF, Schimmer AD, Andreeff M. Mitochondrial ClpP-Mediated Proteolysis Induces Selective Cancer Cell Lethality. Cancer Cell. 2019 May 13;35(5):721-737.e9. doi: 10.1016/j.ccell.2019.03.014. Epub 2019 May 2. PMID: 31056398; PMCID: PMC6620028.

14: Graves PR, Aponte-Collazo LJ, Fennell EMJ, Graves AC, Hale AE, Dicheva N, Herring LE, Gilbert TSK, East MP, McDonald IM, Lockett MR, Ashamalla H, Moorman NJ, Karanewsky DS, Iwanowicz EJ, Holmuhamedov E, Graves LM. Mitochondrial Protease ClpP is a Target for the Anticancer Compounds ONC201 and Related Analogues. ACS Chem Biol. 2019 May 17;14(5):1020-1029. doi: 10.1021/acschembio.9b00222. Epub 2019 May 1. PMID: 31021596; PMCID: PMC6528275.

15: Hall MD, Odia Y, Allen JE, Tarapore R, Khatib Z, Niazi TN, Daghistani D, Schalop L, Chi AS, Oster W, Mehta MP. First clinical experience with DRD2/3 antagonist ONC201 in H3 K27M-mutant pediatric diffuse intrinsic pontine glioma: a case report. J Neurosurg Pediatr. 2019 Apr 5:1-7. doi: 10.3171/2019.2.PEDS18480. Epub ahead of print. PMID: 30952114.

16: Ma Z, Gao G, Fang K, Sun H. Development of Novel Anticancer Agents with a Scaffold of Tetrahydropyrido[4,3-d]pyrimidine-2,4-dione. ACS Med Chem Lett. 2019 Jan 16;10(2):191-195. doi: 10.1021/acsmedchemlett.8b00531. PMID: 30783502; PMCID: PMC6378674.

17: Prabhu VV, Madhukar NS, Gilvary C, Kline CLB, Oster S, El-Deiry WS, Elemento O, Doherty F, VanEngelenburg A, Durrant J, Tarapore RS, Deacon S, Charter N, Jung J, Park DM, Gilbert MR, Rusert J, Wechsler-Reya R, Arrillaga-Romany I, Batchelor TT, Wen PY, Oster W, Allen JE. Dopamine Receptor D5 is a Modulator of Tumor Response to Dopamine Receptor D2 Antagonism. Clin Cancer Res. 2019 Apr 1;25(7):2305-2313. doi: 10.1158/1078-0432.CCR-18-2572. Epub 2018 Dec 17. PMID: 30559168.

18: Fang Z, Wang J, Clark LH, Sun W, Yin Y, Kong W, Pierce SR, West L, Sullivan SA, Tran AQ, Prabhu VV, Zhou C, Bae-Jump V. ONC201 demonstrates anti-tumorigenic and anti-metastatic activity in uterine serous carcinoma in vitro. Am J Cancer Res. 2018 Aug 1;8(8):1551-1563. PMID: 30210923; PMCID: PMC6129479.

19: Bárány P, Oláh RS, Kovács I, Czuczi T, Szabó CL, Takács A, Lajkó E, Láng O, Kőhidai L, Schlosser G, Bősze S, Mező G, Hudecz F, Csámpai A. Ferrocene- Containing Impiridone (ONC201) Hybrids: Synthesis, DFT Modelling, In Vitro Evaluation, and Structure⁻Activity Relationships. Molecules. 2018 Sep 3;23(9):2248. doi: 10.3390/molecules23092248. PMID: 30177664; PMCID: PMC6225426.

20: Ralff MD, Lulla AR, Wagner J, El-Deiry WS. ONC201: a new treatment option being tested clinically for recurrent glioblastoma. Transl Cancer Res. 2017 Oct;6(Suppl 7):S1239-S1243. doi: 10.21037/tcr.2017.10.03. PMID: 30175049; PMCID: PMC6117120.



Additional Information

ONC-201 is an 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, Akt/ERK inhibitor ONC201 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.