ONC201 HCl
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MedKoo CAT#: 206992

CAS#: 1638178-82-1 (HCl)

Description: ONC-201, also known as TIC10, 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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ONC201 HCl
CAS# 1638178-82-1 (HCl)

Theoretical Analysis

MedKoo Cat#: 206992
Name: ONC201 HCl
CAS#: 1638178-82-1 (HCl)
Chemical Formula: C24H28Cl2N4O
Exact Mass:
Molecular Weight: 459.41
Elemental Analysis: C, 62.75; H, 6.14; Cl, 15.43; N, 12.20; O, 3.48

Price and Availability

Size Price Availability Quantity
10.0mg USD 90.0 Ready to ship
25.0mg USD 150.0 Ready to ship
50.0mg USD 250.0 Ready to ship
100.0mg USD 450.0 Ready to ship
200.0mg USD 750.0 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: ONC-201 Dihydrochloride, ONC-201 HCl, ONC201; ONC 201; ONC-201; NSC350625; NSC-350625; NSC 350625; imipridone; TIC10; TIC 10; TIC-10; TRAIL inducing compound 10.

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 dihydrochloride

InChi Key: HKBXPCQCBQFDML-UHFFFAOYSA-N

InChi Code: InChI=1S/C24H26N4O.2ClH/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;2*1H

SMILES Code: O=C1N(CC2=CC=CC=C2C)C3=NCCN3C4=C1CN(CC5=CC=CC=C5)CC4.[H]Cl.[H]Cl

Appearance: 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

Shelf Life: >3 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

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: ONC-201, also known as TIC10 and imipridone, is a small molecule that transcriptionally induces TRAIL in a p53-independent manner and crosses the blood-brain barrier.
In vitro activity: The mechanisms by which NK cells contribute to ONC201 antitumor activity in vitro were futher investigateed. To further explore the potential mechanism of ONC201-induced NK activation and accumulation, a multiplex ELISA-based assay was performed and immune activating and recruiting factors that are upregulated in conditioned media of tumor cells in response to ONC201 treatment were identified. This included IFN-α2a, IL-12p70, and IFN-γ–induced protein 10 (IP-10, or CXCL10) (Figure 7, E and F, and Supplemental Figure 15). Coculture studies of NK cells or conditioned media with tumor cells, including the ONC201-resistant HCT116 Bax–/– cells, confirmed that the ONC201 antitumor effect occurs as a result of ONC201 activation of NK cells, since neither the inactive NK cells nor ONC201 treatment alone significantly induce tumor cytotoxicity in a model that is resistant to direct drug effects (Supplemental Figure 13 and Supplemental Figure 16C). Moreover, addition of the TRAIL-sequestering antibody RIK-2 reduced but did not eliminate the cytotoxic activity toward tumor cells. These results indicate that ONC201 efficacy is potentiated by ONC201 activation of NK cells to produce TRAIL (Figure 7, C and D, and Supplemental Figure 16, C and D). Reference: J Clin Invest. 2018 Jun 1; 128(6): 2325–2338. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983321/
In vivo activity: It was previously established that a single dose of ONC201 can lead to blockade of Akt and ERK that lasts up to 96 hours in vivo. Here it was determined that there was no detectable effect on Akt/ERK or the integrated stress response (ISR) after 30 days following a single ONC201 dose. However, it was found that the dual inhibition of Akt/ERK by ONC201 can still occur in a dose- and frequency-dependent manner in vivo, demonstrating the importance of dose intensification on long-term ONC201 pharmacodynamics in the clinic (Figure 2A). The degree of ISR activation as monitored by CHOP or ATF4 mRNA induction was significantly increased with more frequent me of ONC201 (every 1–2 weeks versus every 3–4 weeks). On the other hand, increasing the ONC201 dose did not further amplify CHOP upregulation at 50 or 100 mg/kg relative to 25 mg/kg given weekly (Figure 2B and Supplemental Figure 4A). We observed a frequency- but not a dose-dependent effect on serum TRAIL levels. Maximum serum TRAIL levels were achieved (150 pg/ml) when ONC201 was administered weekly even at low doses of 25 mg/kg (Figure 2C and Supplemental Figure 4, B and C). Reference: J Clin Invest. 2018 Jun 1; 128(6): 2325–2338. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983321/

Preparing Stock Solutions

The following data is based on the product molecular weight 459.41 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. Wagner J, Kline CL, Zhou L, Campbell KS, MacFarlane AW, Olszanski AJ, Cai KQ, Hensley HH, Ross EA, Ralff MD, Zloza A, Chesson CB, Newman JH, Kaufman H, Bertino J, Stein M, El-Deiry WS. Dose intensification of TRAIL-inducing ONC201 inhibits metastasis and promotes intratumoral NK cell recruitment. J Clin Invest. 2018 Jun 1;128(6):2325-2338. doi: 10.1172/JCI96711. Epub 2018 Apr 30. PMID: 29533922; PMCID: PMC5983321. 2. Greer YE, Porat-Shliom N, Nagashima K, Stuelten C, Crooks D, Koparde VN, Gilbert SF, Islam C, Ubaldini A, Ji Y, Gattinoni L, Soheilian F, Wang X, Hafner M, Shetty J, Tran B, Jailwala P, Cam M, Lang M, Voeller D, Reinhold WC, Rajapakse V, Pommier Y, Weigert R, Linehan WM, Lipkowitz S. ONC201 kills breast cancer cells in vitro by targeting mitochondria. Oncotarget. 2018 Apr 6;9(26):18454-18479. doi: 10.18632/oncotarget.24862. PMID: 29719618; PMCID: PMC5915085. 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.
In vitro protocol: 1. Wagner J, Kline CL, Zhou L, Campbell KS, MacFarlane AW, Olszanski AJ, Cai KQ, Hensley HH, Ross EA, Ralff MD, Zloza A, Chesson CB, Newman JH, Kaufman H, Bertino J, Stein M, El-Deiry WS. Dose intensification of TRAIL-inducing ONC201 inhibits metastasis and promotes intratumoral NK cell recruitment. J Clin Invest. 2018 Jun 1;128(6):2325-2338. doi: 10.1172/JCI96711. Epub 2018 Apr 30. PMID: 29533922; PMCID: PMC5983321. 2. Greer YE, Porat-Shliom N, Nagashima K, Stuelten C, Crooks D, Koparde VN, Gilbert SF, Islam C, Ubaldini A, Ji Y, Gattinoni L, Soheilian F, Wang X, Hafner M, Shetty J, Tran B, Jailwala P, Cam M, Lang M, Voeller D, Reinhold WC, Rajapakse V, Pommier Y, Weigert R, Linehan WM, Lipkowitz S. ONC201 kills breast cancer cells in vitro by targeting mitochondria. Oncotarget. 2018 Apr 6;9(26):18454-18479. doi: 10.18632/oncotarget.24862. PMID: 29719618; PMCID: PMC5915085.
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.Wagner J, Kline CL, Zhou L, Campbell KS, MacFarlane AW, Olszanski AJ, Cai KQ, Hensley HH, Ross EA, Ralff MD, Zloza A, Chesson CB, Newman JH, Kaufman H, Bertino J, Stein M, El-Deiry WS. Dose intensification of TRAIL-inducing ONC201 inhibits metastasis and promotes intratumoral NK cell recruitment. J Clin Invest. 2018 Jun 1;128(6):2325-2338. doi: 10.1172/JCI96711. Epub 2018 Apr 30. PMID: 29533922; PMCID: PMC5983321.

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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.