WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 205945
CAS#: 5291-32-7
Description: APR-246, also known as PRIMA-1MET and Eprenetapopt, is a quinuclidinone derivative that targets the Wrap53 gene with potential antineoplastic activity. p53 activator APR-246 binds to and activates transcription of the Wrap53 gene, which results in an increase in WRAP53 p53 antisense transcript levels and, potentially, an increase in native p53 activity; in turn, increased p53 activity may lead to an induction of cell cycle arrest and apoptosis in tumor cells. This agent may work synergistically with other antineoplastic agents.
MedKoo Cat#: 205945
Name: Eprenetapopt (APR-246)
CAS#: 5291-32-7
Chemical Formula: C10H17NO3
Exact Mass: 199.12084
Molecular Weight: 199.24688
Elemental Analysis: C, 60.28; H, 8.60; N, 7.03; O, 24.09
Synonym: APR246; APR-246; APR 246. PRIMA-1MET; Eprenetapopt;
IUPAC/Chemical Name: 2-(hydroxymethyl)-2-(methoxymethyl)quinuclidin-3-one
InChi Key: BGBNULCRKBVAKL-UHFFFAOYSA-N
InChi Code: InChI=1S/C10H17NO3/c1-14-7-10(6-12)9(13)8-2-4-11(10)5-3-8/h8,12H,2-7H2,1H3
SMILES Code: O=C1C(COC)(CO)N2CCC1CC2
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, DMF, PBS, and EtOH
Shelf Life: >5 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: | APR-246 is a first-in-class, small molecule that restores wild-type p53 functions in TP53-mutant cells. |
| In vitro activity: | Since APR-246 depletes GSH (glutathione) and system xC− blockade leads to cystine starvation, which in turn impairs GSH synthesis, it was examined whether their therapeutic combination would synergistically target mut-p53 cancer cells. APR-246 was applied to esophageal cell lines following SLC7A11 knockdown. Inhibiting SLC7A11 expression significantly enhanced the efficacy of APR-246, particularly against cancer cells with mut-p53 accumulation (Fig. 7a), resulting in synergistic induction of ROS and apoptosis (Fig. 7b,c; Supplementary Fig. 7a). Mechanistically, system xC− blockade in conjunction with APR-246 synergistically depleted intracellular GSH, resulting in mitochondrial ROS (reactive oxygen species) accumulation, lipid peroxidation and ultimately apoptotic cell death (Fig. 7h–k; Supplementary Fig. 7e–h). Reference: Nat Commun. 2017 Mar 28;8:14844. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5379068/ |
| In vivo activity: | In FLO-1 xenografts, SLC7A11 knockdown significantly enhanced the anti-tumour activity of APR-246 (Fig. 8b,c; Supplementary Fig. 8k), leading to synergistic reduction of intratumoral GSH levels and improved animal survival (Fig. 8d,e). Consistent with this, the combination of SAS (sulfasalazine) with APR-246 at tolerated doses (Supplementary Fig. 8l,m) also conferred greater anti-tumour activity than single agents alone (Fig. 8f). Importantly, these findings were reproduced in a PDX model of mut-p53 high-expressing oesophageal cancer (Fig. 8g–i; Supplementary Fig. 8n–o). Analysis of these tumours revealed markedly reduced proliferation and increased apoptosis (Fig. 8j). These results demonstrate the therapeutic potential of combining system xC− inhibitors with APR-246 to synergistically target cancer cells with mut-p53 accumulation. Reference: Nat Commun. 2017 Mar 28;8:14844. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5379068/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 53.33 | 267.65 | |
| Water | 45.0 | 225.85 | |
| Ethanol | 32.5 | 163.11 | |
| DMF | 30.0 | 150.56 | |
| PBS (pH 7.2) | 5.0 | 25.09 |
The following data is based on the product molecular weight 199.24688 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. Liu DS, Duong CP, Haupt S, Montgomery KG, House CM, Azar WJ, Pearson HB, Fisher OM, Read M, Guerra GR, Haupt Y, Cullinane C, Wiman KG, Abrahmsen L, Phillips WA, Clemons NJ. Inhibiting the system xC-/glutathione axis selectively targets cancers with mutant-p53 accumulation. Nat Commun. 2017 Mar 28;8:14844. doi: 10.1038/ncomms14844. PMID: 28348409; PMCID: PMC5379068. |
| In vitro protocol: | 1. Liu DS, Duong CP, Haupt S, Montgomery KG, House CM, Azar WJ, Pearson HB, Fisher OM, Read M, Guerra GR, Haupt Y, Cullinane C, Wiman KG, Abrahmsen L, Phillips WA, Clemons NJ. Inhibiting the system xC-/glutathione axis selectively targets cancers with mutant-p53 accumulation. Nat Commun. 2017 Mar 28;8:14844. doi: 10.1038/ncomms14844. PMID: 28348409; PMCID: PMC5379068. |
| In vivo protocol: | 1. Liu DS, Duong CP, Haupt S, Montgomery KG, House CM, Azar WJ, Pearson HB, Fisher OM, Read M, Guerra GR, Haupt Y, Cullinane C, Wiman KG, Abrahmsen L, Phillips WA, Clemons NJ. Inhibiting the system xC-/glutathione axis selectively targets cancers with mutant-p53 accumulation. Nat Commun. 2017 Mar 28;8:14844. doi: 10.1038/ncomms14844. PMID: 28348409; PMCID: PMC5379068. |
1: Shalom-Feuerstein R, Serror L, Aberdam E, Müller FJ, van Bokhoven H, Wiman KG, Zhou H, Aberdam D, Petit I. Impaired epithelial differentiation of induced pluripotent stem cells from ectodermal dysplasia-related patients is rescued by the small compound APR-246/PRIMA-1MET. Proc Natl Acad Sci U S A. 2013 Feb 5;110(6):2152-6. doi: 10.1073/pnas.1201753109. Epub 2013 Jan 25. PubMed PMID: 23355677.
2: Shen J, van den Bogaard EH, Kouwenhoven EN, Bykov VJ, Rinne T, Zhang Q, Tjabringa GS, Gilissen C, van Heeringen SJ, Schalkwijk J, van Bokhoven H, Wiman KG, Zhou H. APR-246/PRIMA-1MET rescues epidermal differentiation in skin keratinocytes derived from EEC syndrome patients with p63 mutations. Proc Natl Acad Sci U S A. 2013 Feb 5;110(6):2157-62. doi: 10.1073/pnas.1201993110. Epub 2013 Jan 25. PubMed PMID: 23355676.
3: Lehmann S, Bykov VJ, Ali D, Andrén O, Cherif H, Tidefelt U, Uggla B, Yachnin J, Juliusson G, Moshfegh A, Paul C, Wiman KG, Andersson PO. Targeting p53 in vivo: a first-in-human study with p53-targeting compound APR-246 in refractory hematologic malignancies and prostate cancer. J Clin Oncol. 2012 Oct 10;30(29):3633-9. doi: 10.1200/JCO.2011.40.7783. Epub 2012 Sep 10. PubMed PMID: 22965953.
4: Zandi R, Selivanova G, Christensen CL, Gerds TA, Willumsen BM, Poulsen HS. PRIMA-1Met/APR-246 induces apoptosis and tumor growth delay in small cell lung cancer expressing mutant p53. Clin Cancer Res. 2011 May 1;17(9):2830-41. doi: 10.1158/1078-0432.CCR-10-3168. Epub 2011 Mar 17. PubMed PMID: 21415220.
5: Bao W, Chen M, Zhao X, Kumar R, Spinnler C, Thullberg M, Issaeva N, Selivanova G, Strömblad S. PRIMA-1Met/APR-246 induces wild-type p53-dependent suppression of malignant melanoma tumor growth in 3D culture and in vivo. Cell Cycle. 2011 Jan 15;10(2):301-7. Epub 2011 Jan 15. PubMed PMID: 21239882.
6: Ali D, Jönsson-Videsäter K, Deneberg S, Bengtzén S, Nahi H, Paul C, Lehmann S. APR-246 exhibits anti-leukemic activity and synergism with conventional chemotherapeutic drugs in acute myeloid leukemia cells. Eur J Haematol. 2011 Mar;86(3):206-15. doi: 10.1111/j.1600-0609.2010.01557.x. Epub 2011 Jan 11. PubMed PMID: 21114538.
7: Rökaeus N, Shen J, Eckhardt I, Bykov VJ, Wiman KG, Wilhelm MT. PRIMA-1(MET)/APR-246 targets mutant forms of p53 family members p63 and p73. Oncogene. 2010 Dec 9;29(49):6442-51. doi: 10.1038/onc.2010.382. Epub 2010 Sep 6. PubMed PMID: 20818419.
