WARNING: This product is for research use only, not for human or veterinary use.
Hodoodo CAT#: H206933
CAS#: 1807861-48-8
Description: ONC212 is a fluorinated-ONC201 analogue and GPR132 agonist, which shows preclinical efficacy in melanoma and hepatocellular-cancer models. ONC212 is active in pancreatic cancer as single agent or in combination with 5-fluorouracil, irinotecan, oxaliplatin or RTK inhibitor crizotinib. ONC212 exhibited rapid kinetics of activity. ONC212 was further tested in >1000 human cancer cell lines in vitro and evaluated for safety and anti-tumor efficacy in vivo. ONC212 exhibited broad-spectrum efficacy at nanomolar concentrations across solid tumors and hematological malignancies.
Hodoodo Cat#: H206933
Name: ONC-212
CAS#: 1807861-48-8
Chemical Formula: C24H23F3N4O
Exact Mass: 440.1824
Molecular Weight: 440.4702
Elemental Analysis: C, 65.44; H, 5.26; F, 12.94; N, 12.72; O, 3.63
Synonym: ONC212; ONC-212; ONC 212; DUN61488; DUN-61488; DUN 61488;
IUPAC/Chemical Name: 2,4,6,7,8,9-Hexahydro-7-(phenylmethyl)-4-[[4-(trifluoromethyl)phenyl]methyl]imidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(1H)-one
InChi Key: DFULPGUTXZTYKA-UHFFFAOYSA-N
InChi Code: InChI=1S/C24H23F3N4O/c25-24(26,27)19-8-6-18(7-9-19)15-31-22(32)20-16-29(14-17-4-2-1-3-5-17)12-10-21(20)30-13-11-28-23(30)31/h1-9H,10-16H2
SMILES Code: O=C1N(CC2=CC=C(C(F)(F)F)C=C2)C3=NCCN3C4=C1CN(CC5=CC=CC=C5)CC4
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: >2 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: | ONC212, a fluorinated-ONC201 analogue, is a promising anti-cancer agent and also a selective agonist of GPR132. |
| In vitro activity: | ONC‐212 induced a significant (P < .05) accumulation of cells from both the OSU‐CLL and OSU‐CLL‐TP53ko lines in G0/G1, with a concomitant decrease in the proportion of cells in G2/M at each of the three time points (P < .05; Figure 2A). In the TP53ko cells, a significant (P < .05) increase in the proportion of cells in S phase was also observed with ONC‐212 treatment at each time point. Reference: EJHaem. 2021 Jan 14;2(1):81-93. https://pubmed.ncbi.nlm.nih.gov/35846080/ |
| In vivo activity: | Immunohistochemical analyses of Ki67 and caspase-3 demonstrated that ONC212 reduced tumor-cell proliferation and induced apoptosis in UACC-903 and MALME xenografts to a greater extent than ONC201 (Fig. 7d, Fig. S4c). Reference: Cell Cycle. 2017 Oct 2;16(19):1790-1799. https://pubmed.ncbi.nlm.nih.gov/28489985/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMF | 1.0 | 2.27 | |
| DMSO | 25.5 | 57.89 | |
| DMSO:PBS (pH 7.2) (1:3) | 0.25 | 0.57 |
The following data is based on the product molecular weight 440.4702 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.
| 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. Ferrarini I, Louie A, Zhou L, El-Deiry WS. ONC212 is a Novel Mitocan Acting Synergistically with Glycolysis Inhibition in Pancreatic Cancer. Mol Cancer Ther. 2021 Sep;20(9):1572-1583. doi: 10.1158/1535-7163.MCT-20-0962. Epub 2021 Jun 17. PMID: 34224362; PMCID: PMC8419089. 2. Fatima N, Shen Y, Crassini K, Iwanowicz EJ, Lang H, Karanewsky DS, Christopherson RI, Mulligan SP, Best OG. The ClpP activator ONC-212 (TR-31) inhibits BCL2 and B-cell receptor signaling in CLL. EJHaem. 2021 Jan 14;2(1):81-93. doi: 10.1002/jha2.160. PMID: 35846080; PMCID: PMC9175891. 3. Wagner J, Kline CL, Ralff MD, Lev A, Lulla A, Zhou L, Olson GL, Nallaganchu BR, Benes CH, Allen JE, Prabhu VV, Stogniew M, Oster W, El-Deiry WS. Preclinical evaluation of the imipridone family, analogs of clinical stage anti-cancer small molecule ONC201, reveals potent anti-cancer effects of ONC212. Cell Cycle. 2017 Oct 2;16(19):1790-1799. doi: 10.1080/15384101.2017.1325046. Epub 2017 May 10. PMID: 28489985; PMCID: PMC5628644. 4. Lev A, Lulla AR, Wagner J, Ralff MD, Kiehl JB, Zhou Y, Benes CH, Prabhu VV, Oster W, Astsaturov I, Dicker DT, El-Deiry WS. Anti-pancreatic cancer activity of ONC212 involves the unfolded protein response (UPR) and is reduced by IGF1-R and GRP78/BIP. Oncotarget. 2017 Sep 12;8(47):81776-81793. doi: 10.18632/oncotarget.20819. PMID: 29137221; PMCID: PMC5669847. |
| In vitro protocol: | 1. Ferrarini I, Louie A, Zhou L, El-Deiry WS. ONC212 is a Novel Mitocan Acting Synergistically with Glycolysis Inhibition in Pancreatic Cancer. Mol Cancer Ther. 2021 Sep;20(9):1572-1583. doi: 10.1158/1535-7163.MCT-20-0962. Epub 2021 Jun 17. PMID: 34224362; PMCID: PMC8419089. 2. Fatima N, Shen Y, Crassini K, Iwanowicz EJ, Lang H, Karanewsky DS, Christopherson RI, Mulligan SP, Best OG. The ClpP activator ONC-212 (TR-31) inhibits BCL2 and B-cell receptor signaling in CLL. EJHaem. 2021 Jan 14;2(1):81-93. doi: 10.1002/jha2.160. PMID: 35846080; PMCID: PMC9175891. |
| In vivo protocol: | 1. Wagner J, Kline CL, Ralff MD, Lev A, Lulla A, Zhou L, Olson GL, Nallaganchu BR, Benes CH, Allen JE, Prabhu VV, Stogniew M, Oster W, El-Deiry WS. Preclinical evaluation of the imipridone family, analogs of clinical stage anti-cancer small molecule ONC201, reveals potent anti-cancer effects of ONC212. Cell Cycle. 2017 Oct 2;16(19):1790-1799. doi: 10.1080/15384101.2017.1325046. Epub 2017 May 10. PMID: 28489985; PMCID: PMC5628644. 2. Lev A, Lulla AR, Wagner J, Ralff MD, Kiehl JB, Zhou Y, Benes CH, Prabhu VV, Oster W, Astsaturov I, Dicker DT, El-Deiry WS. Anti-pancreatic cancer activity of ONC212 involves the unfolded protein response (UPR) and is reduced by IGF1-R and GRP78/BIP. Oncotarget. 2017 Sep 12;8(47):81776-81793. doi: 10.18632/oncotarget.20819. PMID: 29137221; PMCID: PMC5669847. |
1: Raufi AG, Liguori NR, Carlsen L, Parker C, Hernandez Borrero L, Zhang S, Tian X, Louie A, Zhou L, Seyhan AA, El-Deiry WS. Therapeutic Targeting of Autophagy in Pancreatic Ductal Adenocarcinoma. Front Pharmacol. 2021 Nov 30;12:751568. doi: 10.3389/fphar.2021.751568. PMID: 34916936; PMCID: PMC8670090.
2: Fuchs E, Messerer DAC, Karpel-Massler G, Fauler M, Zimmer T, Jungwirth B, Föhr KJ. Block of Voltage-Gated Sodium Channels as a Potential Novel Anti-cancer Mechanism of TIC10. Front Pharmacol. 2021 Oct 21;12:737637. doi: 10.3389/fphar.2021.737637. PMID: 34744721; PMCID: PMC8567104.
3: Borsuk R, Zhou L, Chang WI, Zhang Y, Sharma A, Prabhu VV, Tapinos N, Lulla RR, El-Deiry WS. Potent preclinical sensitivity to imipridone-based combination therapies in oncohistone H3K27M-mutant diffuse intrinsic pontine glioma is associated with induction of the integrated stress response, TRAIL death receptor DR5, reduced ClpX and apoptosis. Am J Cancer Res. 2021 Sep 15;11(9):4607-4623. PMID: 34659909; PMCID: PMC8493379.
4: Ferrarini I, Louie A, Zhou L, El-Deiry WS. ONC212 is a Novel Mitocan Acting Synergistically with Glycolysis Inhibition in Pancreatic Cancer. Mol Cancer Ther. 2021 Sep;20(9):1572-1583. doi: 10.1158/1535-7163.MCT-20-0962. Epub 2021 Jun 17. PMID: 34224362; PMCID: PMC8419089.
5: Yang T, Zhang T, Zhou X, Wang P, Gan J, Song B, Yang S, Yang CG. Dysregulation of ClpP by Small-Molecule Activators Used Against Xanthomonas oryzae pv. oryzae Infections. J Agric Food Chem. 2021 Jul 14;69(27):7545-7553. doi: 10.1021/acs.jafc.1c01470. Epub 2021 Jul 3. PMID: 34218658.
6: Bonner ER, Waszak SM, Grotzer MA, Mueller S, Nazarian J. Mechanisms of imipridones in targeting mitochondrial metabolism in cancer cells. Neuro Oncol. 2021 Apr 12;23(4):542-556. doi: 10.1093/neuonc/noaa283. PMID: 33336683; PMCID: PMC8041338.
7: Carter JL, Hege K, Kalpage HA, Edwards H, Hüttemann M, Taub JW, Ge Y. Targeting mitochondrial respiration for the treatment of acute myeloid leukemia. Biochem Pharmacol. 2020 Dec;182:114253. doi: 10.1016/j.bcp.2020.114253. Epub 2020 Oct 2. PMID: 33011159; PMCID: PMC8073742.
8: Aminzadeh-Gohari S, Weber DD, Catalano L, Feichtinger RG, Kofler B, Lang R. Targeting Mitochondria in Melanoma. Biomolecules. 2020 Sep 30;10(10):1395. doi: 10.3390/biom10101395. PMID: 33007949; PMCID: PMC7599575.
9: 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.
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: 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.
12: Ishida CT, Zhang Y, Bianchetti E, Shu C, Nguyen TTT, Kleiner G, Sanchez- Quintero MJ, Quinzii CM, Westhoff MA, Karpel-Massler G, Prabhu VV, Allen JE, Siegelin MD. Metabolic Reprogramming by Dual AKT/ERK Inhibition through Imipridones Elicits Unique Vulnerabilities in Glioblastoma. Clin Cancer Res. 2018 Nov 1;24(21):5392-5406. doi: 10.1158/1078-0432.CCR-18-1040. Epub 2018 Jul 23. PMID: 30037819; PMCID: PMC6214769.
13: Lev A, Lulla AR, Wagner J, Ralff MD, Kiehl JB, Zhou Y, Benes CH, Prabhu VV, Oster W, Astsaturov I, Dicker DT, El-Deiry WS. Anti-pancreatic cancer activity of ONC212 involves the unfolded protein response (UPR) and is reduced by IGF1-R and GRP78/BIP. Oncotarget. 2017 Sep 12;8(47):81776-81793. doi: 10.18632/oncotarget.20819. PMID: 29137221; PMCID: PMC5669847.
14: Wagner J, Kline CL, Ralff MD, Lev A, Lulla A, Zhou L, Olson GL, Nallaganchu BR, Benes CH, Allen JE, Prabhu VV, Stogniew M, Oster W, El-Deiry WS. Preclinical evaluation of the imipridone family, analogs of clinical stage anti-cancer small molecule ONC201, reveals potent anti-cancer effects of ONC212. Cell Cycle. 2017 Oct 2;16(19):1790-1799. doi: 10.1080/15384101.2017.1325046. Epub 2017 May 10. PMID: 28489985; PMCID: PMC5628644.
Skin cancer emerged as a tumor type with improved efficacy relative to ONC201. Orally administered ONC212 displayed potent anti-tumor effects in vivo, a broad therapeutic window and a favorable PK profile. ONC212 was efficacious in vivo in BRAF V600E melanoma models that are less sensitive to ONC201. Based on these findings, ONC212 warrants further development as a drug candidate. It is clear that therapeutic utility extends beyond ONC201 to include additional imipridones.
ONC212 exerted potent and prominent apoptogenic effects on acute myeloid leukemia (AML) and mantle cell lymphoma (MCL) cell lines (e.g., ED50s of 141.0 nM in p53 wild-type OCI-AML3 cells, 105.7 nM in MOLM13 cells, and 265.2 nM in p53-null JeKo-1 cell lines).
