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MedKoo Cat#: 205892 | Name: Pinometostat
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Description:

WARNING: This product is for research use only, not for human or veterinary use.

Pinometostat, also known as EPZ-5676, is a small molecule inhibitor of histone methyltransferase with potential antineoplastic activity. Upon intravenous administration, EPZ-5676 specifically blocks the activity of the histone lysine-methyltransferase DOT1L, thereby inhibiting the methylation of nucleosomal histone H3 on lysine 79 (H3K79) that is bound to the mixed lineage leukemia (MLL) fusion protein which targets genes and blocks the expression of leukemogenic genes.

Chemical Structure

Pinometostat
Pinometostat
CAS#1380288-87-8

Theoretical Analysis

MedKoo Cat#: 205892

Name: Pinometostat

CAS#: 1380288-87-8

Chemical Formula: C30H42N8O3

Exact Mass: 562.3380

Molecular Weight: 562.71

Elemental Analysis: C, 64.03; H, 7.52; N, 19.91; O, 8.53

Price and Availability

Size Price Availability Quantity
5mg USD 90.00 Ready to ship
10mg USD 150.00 Ready to ship
25mg USD 250.00 Ready to ship
50mg USD 450.00 Ready to ship
100mg USD 750.00 Ready to ship
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Related CAS #
No Data
Synonym
EPZ5676; EPZ-5676; EPZ 5676; Pinometostat.
IUPAC/Chemical Name
(2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol
InChi Key
LXFOLMYKSYSZQS-LURJZOHASA-N
InChi Code
InChI=1S/C30H42N8O3/c1-16(2)37(13-22-25(39)26(40)29(41-22)38-15-34-24-27(31)32-14-33-28(24)38)19-10-17(11-19)6-9-23-35-20-8-7-18(30(3,4)5)12-21(20)36-23/h7-8,12,14-17,19,22,25-26,29,39-40H,6,9-11,13H2,1-5H3,(H,35,36)(H2,31,32,33)/t17-,19+,22-,25-,26-,29-/m1/s1
SMILES Code
O[C@H]1[C@H](N2C=NC3=C(N)N=CN=C23)O[C@H](CN([C@H]4C[C@@H](CCC5=NC6=CC(C(C)(C)C)=CC=C6N5)C4)C(C)C)[C@H]1O
Appearance
Solid powder
Purity
>99% (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 in water
Shelf Life
>2 years if stored properly
Drug Formulation
Stock solutions (50 or 10 mM) were prepared in dimethylsulfoxide (DMSO) and stored at −20°C.
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
More Info
Biological target:
Pinometostat (EPZ-5676) is a DOT1L histone methyltransferase inhibitor with a Ki of 80 pM.
In vitro activity:
EPZ5676, a DOT1L inhibitor approved for use in clinical trials, is less toxic and more effective than EPZ004777. Here, this study found that EPZ5676 was more efficient than EPZ004777 in down-regulating HOXA9, PBX3 and H3K79m2 expression in human NPMc+ cells (Figure S5A), and in promoting cell apoptosis (Figure S5B). EPZ5676 gradually reduced HOXA9 and PBX3 expression in OCI-AML3 cells as the treatment time increased. The levels of cleaved caspase 3 and PARP were also increased by EPZ5676 treatment in a time-dependent manner (Figure 5A). These changes were not observed in OCI-AML2 cells (Figure 5A). The two cell lines were treated with EPZ5676 for 3 days or 7 days and then were stained with Annexin V/PI for apoptosis detection. EPZ5676 induced a higher percentage of apoptotic cells in the OCI-AML3 line than in the OCI-AML2 line on both day 3 and day 7 (Figure 5B). Additionally, a decrease in HOXA9 and PBX3 expression and an increase in the expression of apoptosis-related proteins and the number of apoptotic cells were detected only in KG-1 cells stably transduced with mutant NPM1 but not in those transduced with the vector or WT NPM1 after 7 days of treatment with EPZ5676 (Figure 5C-D). Reference: Theranostics. 2018 Jul 30;8(16):4359-4371. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134928/
In vivo activity:
Mononuclear cells (MNCs) accumulated significantly in the liver and spleen of P. acnes-primed control mice (Figure 2A), and both the percentage and absolute number of CD4+ T cells increased dramatically in the liver and spleen (Figure 2B and C). By contrast, infiltration of MNCs and CD4+ T cells decreased significantly both in the liver and spleen of EPZ-5676–treated mice (Figure 2A–C). To detect the proliferation of CD4+ T cells, the study injected BrdU (5-bromo-2-deoxyuridine), a synthetic nucleoside that could be incorporated into newly synthesized DNA to monitor the cell proliferation, into EPZ-5676–treated or P. acnes-primed control mice. The flow cytometric analysis revealed that EPZ-5676 treatment decreased the frequencies of BrdU+ CD4+ T cells in the liver and spleen after P. acnes priming (Figure 2D), suggesting that Dot1L inhibition may regulate the proliferation of CD4+ T cells in vivo. In addition, EPZ-5676–treated mice showed decreased CD44hiCD62Llo CD4+ T cells, and increased CD62LhiCD44lo CD4+ T cells (Figure 2E), suggesting that Dot1L inhibition suppressed CD4+ T cell activation in vivo. The study also found reduced expression of chemokine receptors, such as CXCR3 and CCR7 on CD4+ T cells (Figure 3A and B) and their respective chemokines CXCL9, CXCL10, and CCL21 in the liver of EPZ-5676–treated mice (Figure 3C). These results indicated that Dot1L inhibition also suppressed the chemotaxis of pathogenic CD4+ T cells into the liver. Reference: Cell Mol Gastroenterol Hepatol. 2021 Jan 23;12(1):81-98. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081916/
Solvent mg/mL mM
Solubility
DMSO 57.6 102.36
DMF 30.0 53.31
Ethanol 65.0 115.51
Ethanol:PBS (pH 7.2) (1:8) 0.1 0.18
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 562.71 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. Godfrey L, Crump NT, Thorne R, Lau IJ, Repapi E, Dimou D, Smith AL, Harman JR, Telenius JM, Oudelaar AM, Downes DJ, Vyas P, Hughes JR, Milne TA. DOT1L inhibition reveals a distinct subset of enhancers dependent on H3K79 methylation. Nat Commun. 2019 Jun 26;10(1):2803. doi: 10.1038/s41467-019-10844-3. PMID: 31243293; PMCID: PMC6594956. 2. Zhang W, Zhao C, Zhao J, Zhu Y, Weng X, Chen Q, Sun H, Mi JQ, Li J, Zhu J, Chen Z, Pandolfi PP, Chen S, Yan X, Xu J. Inactivation of PBX3 and HOXA9 by down-regulating H3K79 methylation represses NPM1-mutated leukemic cell survival. Theranostics. 2018 Jul 30;8(16):4359-4371. doi: 10.7150/thno.26900. PMID: 30214626; PMCID: PMC6134928. 3. Yang W, Yu H, Huang J, Miao X, Wang Q, Wang Y, Cheng Y, He S, Zhao F, Meng L, Wang B, Qian F, Ren X, Jin M, Gu Y, Zhang Y, Cai W. Inhibition of Dot1L Alleviates Fulminant Hepatitis Through Myeloid-Derived Suppressor Cells. Cell Mol Gastroenterol Hepatol. 2021 Jan 23;12(1):81-98. doi: 10.1016/j.jcmgh.2021.01.013. Epub ahead of print. PMID: 33497867; PMCID: PMC8081916. 4. Song Z, Wei Z, Wang Q, Zhang X, Tao X, Wu N, Liu X, Qian J. The role of DOT1L in the proliferation and prognosis of gastric cancer. Biosci Rep. 2020 Jan 31;40(1):BSR20193515. doi: 10.1042/BSR20193515. PMID: 31939604; PMCID: PMC6997103.
In vitro protocol:
1. Godfrey L, Crump NT, Thorne R, Lau IJ, Repapi E, Dimou D, Smith AL, Harman JR, Telenius JM, Oudelaar AM, Downes DJ, Vyas P, Hughes JR, Milne TA. DOT1L inhibition reveals a distinct subset of enhancers dependent on H3K79 methylation. Nat Commun. 2019 Jun 26;10(1):2803. doi: 10.1038/s41467-019-10844-3. PMID: 31243293; PMCID: PMC6594956. 2. Zhang W, Zhao C, Zhao J, Zhu Y, Weng X, Chen Q, Sun H, Mi JQ, Li J, Zhu J, Chen Z, Pandolfi PP, Chen S, Yan X, Xu J. Inactivation of PBX3 and HOXA9 by down-regulating H3K79 methylation represses NPM1-mutated leukemic cell survival. Theranostics. 2018 Jul 30;8(16):4359-4371. doi: 10.7150/thno.26900. PMID: 30214626; PMCID: PMC6134928.
In vivo protocol:
1. Yang W, Yu H, Huang J, Miao X, Wang Q, Wang Y, Cheng Y, He S, Zhao F, Meng L, Wang B, Qian F, Ren X, Jin M, Gu Y, Zhang Y, Cai W. Inhibition of Dot1L Alleviates Fulminant Hepatitis Through Myeloid-Derived Suppressor Cells. Cell Mol Gastroenterol Hepatol. 2021 Jan 23;12(1):81-98. doi: 10.1016/j.jcmgh.2021.01.013. Epub ahead of print. PMID: 33497867; PMCID: PMC8081916. 2. Song Z, Wei Z, Wang Q, Zhang X, Tao X, Wu N, Liu X, Qian J. The role of DOT1L in the proliferation and prognosis of gastric cancer. Biosci Rep. 2020 Jan 31;40(1):BSR20193515. doi: 10.1042/BSR20193515. PMID: 31939604; PMCID: PMC6997103.
1: Adriaanse FRS, Schneider P, Arentsen-Peters STCJM, Fonseca AMND, Stutterheim J, Pieters R, Zwaan CM, Stam RW. Distinct Responses to Menin Inhibition and Synergy with DOT1L Inhibition in KMT2A-Rearranged Acute Lymphoblastic and Myeloid Leukemia. Int J Mol Sci. 2024 May 30;25(11):6020. doi: 10.3390/ijms25116020. PMID: 38892207; PMCID: PMC11173273. 2: Visamol S, Palaga T, Saonanon P, Pruksakorn V, Hirankarn N, van Hagen PM, Dik WA, Virakul S. EZH2 as a major histone methyltransferase in PDGF-BB-activated orbital fibroblast in the pathogenesis of Graves' ophthalmopathy. Sci Rep. 2024 Apr 4;14(1):7947. doi: 10.1038/s41598-024-57926-x. PMID: 38575707; PMCID: PMC10994939. 3: Schneider P, Crump NT, Arentsen-Peters STCJM, Smith AL, Hagelaar R, Adriaanse FRS, Bos RS, de Jong A, Nierkens S, Koopmans B, Milne TA, Pieters R, Stam RW. Modelling acquired resistance to DOT1L inhibition exhibits the adaptive potential of KMT2A-rearranged acute lymphoblastic leukemia. Exp Hematol Oncol. 2023 Sep 22;12(1):81. doi: 10.1186/s40164-023-00445-8. PMID: 37740239; PMCID: PMC10517487. 4: Shirasu T, Yodsanit N, Li J, Huang Y, Xie X, Tang R, Wang Q, Zhang M, Urabe G, Webb A, Wang Y, Wang X, Xie R, Wang B, Kent KC, Gong S, Guo LW. Neointima abating and endothelium preserving - An adventitia-localized nanoformulation to inhibit the epigenetic writer DOT1L. Biomaterials. 2023 Oct;301:122245. doi: 10.1016/j.biomaterials.2023.122245. Epub 2023 Jul 13. PMID: 37467597; PMCID: PMC10530408. 5: Khirsariya P, Pospíšil P, Maier L, Boudný M, Babáš M, Kroutil O, Mráz M, Vácha R, Paruch K. Synthesis and Profiling of Highly Selective Inhibitors of Methyltransferase DOT1L Based on Carbocyclic C-Nucleosides. J Med Chem. 2022 Apr 14;65(7):5701-5723. doi: 10.1021/acs.jmedchem.1c02228. Epub 2022 Mar 18. PMID: 35302777. 6: Bon C, Si Y, Pernak M, Barbachowska M, Levi-Acobas E, Cadet Daniel V, Jallet C, Ruzic D, Djokovic N, Djikić T, Nikolic K, Halby L, Arimondo PB. Synthesis and Biological Activity of a Cytostatic Inhibitor of MLLr Leukemia Targeting the DOT1L Protein. Molecules. 2021 Aug 31;26(17):5300. doi: 10.3390/molecules26175300. PMID: 34500733; PMCID: PMC8434109. 7: Richter WF, Shah RN, Ruthenburg AJ. Non-canonical H3K79me2-dependent pathways promote the survival of MLL-rearranged leukemia. Elife. 2021 Jul 15;10:e64960. doi: 10.7554/eLife.64960. PMID: 34263728; PMCID: PMC8315800. 8: Grieselhuber NR, Mims AS. Novel Targeted Therapeutics in Acute Myeloid Leukemia: an Embarrassment of Riches. Curr Hematol Malig Rep. 2021 Apr;16(2):192-206. doi: 10.1007/s11899-021-00621-9. Epub 2021 Mar 18. PMID: 33738705; PMCID: PMC8515252. 9: Lonetti A, Indio V, Laginestra MA, Tarantino G, Chiarini F, Astolfi A, Bertuccio SN, Martelli AM, Locatelli F, Pession A, Masetti R. Inhibition of Methyltransferase DOT1L Sensitizes to Sorafenib Treatment AML Cells Irrespective of MLL-Rearrangements: A Novel Therapeutic Strategy for Pediatric AML. Cancers (Basel). 2020 Jul 20;12(7):1972. doi: 10.3390/cancers12071972. PMID: 32698374; PMCID: PMC7409321. 10: Sarno F, Nebbioso A, Altucci L. DOT1L: a key target in normal chromatin remodelling and in mixed-lineage leukaemia treatment. Epigenetics. 2020 May;15(5):439-453. doi: 10.1080/15592294.2019.1699991. Epub 2019 Dec 28. PMID: 31790636; PMCID: PMC7188393. 11: Marcos-Villar L, Nieto A. The DOT1L inhibitor Pinometostat decreases the host-response against infections: Considerations about its use in human therapy. Sci Rep. 2019 Nov 14;9(1):16862. doi: 10.1038/s41598-019-53239-6. PMID: 31727944; PMCID: PMC6856118. 12: Stein EM, Garcia-Manero G, Rizzieri DA, Tibes R, Berdeja JG, Savona MR, Jongen-Lavrenic M, Altman JK, Thomson B, Blakemore SJ, Daigle SR, Waters NJ, Suttle AB, Clawson A, Pollock R, Krivtsov A, Armstrong SA, DiMartino J, Hedrick E, Löwenberg B, Tallman MS. The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia. Blood. 2018 Jun 14;131(24):2661-2669. doi: 10.1182/blood-2017-12-818948. Epub 2018 May 3. PMID: 29724899; PMCID: PMC6265654. 13: Campbell CT, Haladyna JN, Drubin DA, Thomson TM, Maria MJ, Yamauchi T, Waters NJ, Olhava EJ, Pollock RM, Smith JJ, Copeland RA, Blakemore SJ, Bernt KM, Daigle SR. Mechanisms of Pinometostat (EPZ-5676) Treatment-Emergent Resistance in MLL-Rearranged Leukemia. Mol Cancer Ther. 2017 Aug;16(8):1669-1679. doi: 10.1158/1535-7163.MCT-16-0693. Epub 2017 Apr 20. PMID: 28428443. 14: Waters NJ. Preclinical Pharmacokinetics and Pharmacodynamics of Pinometostat (EPZ-5676), a First-in-Class, Small Molecule S-Adenosyl Methionine Competitive Inhibitor of DOT1L. Eur J Drug Metab Pharmacokinet. 2017 Dec;42(6):891-901. doi: 10.1007/s13318-017-0404-3. PMID: 28229434. 15: Smith SA, Gagnon S, Waters NJ. Mechanistic investigations into the species differences in pinometostat clearance: impact of binding to alpha-1-acid glycoprotein and permeability-limited hepatic uptake. Xenobiotica. 2017 Mar;47(3):185-193. doi: 10.3109/00498254.2016.1173265. Epub 2016 May 10. PMID: 27160567. 16: Rioux N, Waters NJ. Physiologically Based Pharmacokinetic Modeling in Pediatric Oncology Drug Development. Drug Metab Dispos. 2016 Jul;44(7):934-43. doi: 10.1124/dmd.115.068031. Epub 2016 Mar 2. PMID: 26936973. 17: Waters NJ, Smith SA, Olhava EJ, Duncan KW, Burton RD, O'Neill J, Rodrigue ME, Pollock RM, Moyer MP, Chesworth R. Metabolism and disposition of the DOT1L inhibitor, pinometostat (EPZ-5676), in rat, dog and human. Cancer Chemother Pharmacol. 2016 Jan;77(1):43-62. doi: 10.1007/s00280-015-2929-y. Epub 2015 Dec 8. PMID: 26645404. 18: Waters NJ, Daigle SR, Rehlaender BN, Basavapathruni A, Campbell CT, Jensen TB, Truitt BF, Olhava EJ, Pollock RM, Stickland KA, Dovletoglou A. Exploring drug delivery for the DOT1L inhibitor pinometostat (EPZ-5676): Subcutaneous administration as an alternative to continuous IV infusion, in the pursuit of an epigenetic target. J Control Release. 2015 Dec 28;220(Pt B):758-65. doi: 10.1016/j.jconrel.2015.09.023. Epub 2015 Sep 15. PMID: 26385168.