EPZ5676

DOT1L inhibitor,potent and SAM competitive CAS# 1380288-87-8

EPZ5676

Catalog No. BCC2215----Order now to get a substantial discount!

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Chemical structure

EPZ5676

3D structure

Chemical Properties of EPZ5676

Cas No. 1380288-87-8 SDF Download SDF
PubChem ID 57345410 Appearance Powder
Formula C30H42N8O3 M.Wt 562.71
Type of Compound N/A Storage Desiccate at -20°C
Synonyms Pinometostat
Solubility DMSO : ≥ 47.8 mg/mL (84.95 mM)
*"≥" means soluble, but saturation unknown.
Chemical Name (2R,3R,4S,5R)-2-(6-aminopurin-9-yl)-5-[[[3-[2-(6-tert-butyl-1H-benzimidazol-2-yl)ethyl]cyclobutyl]-propan-2-ylamino]methyl]oxolane-3,4-diol
SMILES CC(C)N(CC1C(C(C(O1)N2C=NC3=C2N=CN=C3N)O)O)C4CC(C4)CCC5=NC6=C(N5)C=C(C=C6)C(C)(C)C
Standard InChIKey LXFOLMYKSYSZQS-XKHGBIBOSA-N
Standard InChI 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
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of EPZ5676

DescriptionEPZ5676 is a potent and selective inhibitor of DOT1L methyltransferase with Ki value of 80 pM.
TargetsDOT1L    
IC5080 pM (Ki)     

Protocol

Cell Assay [1]
To analyse inhibition of histone methylation in MV4-11 cells following EPZ-5676 treatment, extracted histones (400 ng) are fractionated on a 10-20% Tris HCl gels with Tris-Glycine SDS running buffer under denaturing conditions and transferred to nitrocellulose filters. Filters are cut into strips and incubated for 1 hour in blocking buffer at room temperature (RT) and then incubated overnight at 4°C in blocking buffer. Filters are washed 3 times for 5 minutes with wash buffer (Phosphate buffered saline (PBS) including 0.01% Tween 20 (PBST)) and incubated with infrared tagged secondary antibody at RT for 1 hour. Filters are washed in PBST and reprobed for 1 hour at RT with the appropriate total histone antibody control (mouse anti-histone H3 (1:20,000), CST 3638, or mouse anti-histone H4 (1:10,000), CST 2935). Filters are washed again in PBST and incubated with infrared tagged secondary antibody (IRDye 800Cw donkey-anti-mouse IgG (1:20,000), Li-Cor 926-32212) at RT for 1 hour. After a final ish in PBST, filters are scanned using the Odyssey infared imager (Li-cor). To analyse inhibition of H3K79 methylation in peripheral blood mononuclear cells (PBMCs) from rats dosed with EPZ-5676, 20 μL of PBMC whole cell lysate is fractionated on denaturing gels and analysed by immunoblotting with antibodies to H3K79me2 or total H3. Signal intensities specific for the H3K79me2 antibody and total histone H3 control antibody are quantified using Odyssey software. The H3K79me2 signal intensity is normalized by dividing it by the total histone H3 control signal intensity in the same lane.

Animal Administration [1]
0.2 mL of a MV4-11 cell suspension (1×107 cells) in PBS is injected subcutaneously into female athymic nude mice (Crl:NU(Ncr)-Foxn1nu). Tumors are measured by calipers and mice are randomized according to tumor size into treatment groups (n=10) before the initiation of dosing with EPZ-5676 when tumor volumes reache approximately 100 mma3. EPZ-5676 is administered intraperitoneally three times daily for 28 days at 10 and 20 mg/kg in 10% ethanol in saline. Mice are weighed and tumors measured with calipers twice weekly until the end of the study.

References:
[1]. Daigle SR, et al. Potent inhibition of DOT1L as treatment for MLL-fusion leukemia. Blood. 2013 Jun 25. [Epub ahead of print] [2]. Klaus CR, et al. DOT1L inhibitor EPZ-5676 displays synergistic antiproliferative activity in combination with standard of care drugs and hypomethylating agents in MLL-rearranged leukemia cells. J Pharmacol Exp Ther. 2014 Sep;350(3):646-56.

EPZ5676 Dilution Calculator

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EPZ5676 Molarity Calculator

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Preparing Stock Solutions of EPZ5676

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.7771 mL 8.8856 mL 17.7711 mL 35.5423 mL 44.4279 mL
5 mM 0.3554 mL 1.7771 mL 3.5542 mL 7.1085 mL 8.8856 mL
10 mM 0.1777 mL 0.8886 mL 1.7771 mL 3.5542 mL 4.4428 mL
50 mM 0.0355 mL 0.1777 mL 0.3554 mL 0.7108 mL 0.8886 mL
100 mM 0.0178 mL 0.0889 mL 0.1777 mL 0.3554 mL 0.4443 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on EPZ5676

EPZ5676 is a potent inhibitor of DOT1L histone methyltransferase, according to X-ray crystallographic analysis, that occupies the S-adenosyl methionine (SAM) binding pocket of DOT1L and induces conformational changes in DOT1L resulting in the opening of a hydrophobic pocket beyond the amino acid portion of SAM. EPZ5676 selectively inhibits DOTIL with a value of 50% inhibition concentration IC50 of 0.8 nM, which is 37000-fold greater in selectivity than other methyltransferases, including CARM1, EHMT1/2, EZH1/2, PRMT1/2/5/6/8, SETD7, SMYD2/3, and WHSC1/1L1. EPZ5676 has been investigated for the treatment of MLL-rearranged leukemia in multiple studies where results have shown that EPZ5676 inhibits H3K79 methylation and the expression of MLL-fusion target gene and potently kills acute leukemia cell lines bearing MLL translocation.

Reference

Daigle SR, Olhava EJ, Therkelsen CA, Basavapathruni A, Jin L, Boriack-Sjodin PA, Allain CJ, Klaus CR, Raimondi A, Scott MP, Waters NJ, Chesworth R, Moyer MP, Copeland RA, Richon VM, Pollock RM. Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. Blood. 2013 Aug 8;122(6):1017-1025.

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References on EPZ5676

Tri-methylation of H3K79 is decreased in TGF-beta1-induced epithelial-to-mesenchymal transition in lung cancer.[Pubmed:28804523]

Clin Epigenetics. 2017 Aug 8;9:80.

BACKGROUND: The epithelial-to-mesenchymal transition (EMT) enables epithelial cancer cells to acquire mesenchymal features and contributes to metastasis and resistance to treatment. This process involves epigenetic reprogramming for gene expression. We explored global histone modifications during TGF-beta1-induced EMT in two non-small cell lung cancer (NSCLC) cell lines and tested different epigenetic treatment to modulate or partially reverse EMT. RESULTS: Loss of classical epithelial markers and gain of mesenchymal markers were verified in A549 and H358 cell lines during TGF-beta1-induced EMT. In addition, we noticed increased expression of the axonal guidance protein semaphorin 3C (SEMA3C) and PD-L1 (programmed death-ligand 1) involved in the inhibition of the immune system, suggesting that both SEMA3C and PD-L1 could be the new markers of TGF-beta1-induced EMT. H3K79me3 and H2BK120me1 were decreased in A549 and H358 cell lines after a 48-h TGF-beta1 treatment, as well as H2BK120ac in A549 cells. However, decreased H3K79me3 was not associated with expression of the histone methyltransferase DOT1L. Furthermore, H3K79me3 was decreased in tumors compared in normal tissues and not associated with cell proliferation. Associations of histone deacetylase inhibitor (SAHA) with DOT1L inhibitors (EPZ5676 or SGC0946) or BET bromodomain inhibitor (PFI-1) were efficient to partially reverse TGF-beta1 effects by decreasing expression of PD-L1, SEMA3C, and its receptor neuropilin-2 (NRP2) and by increasing epithelial markers such as E-cadherin. CONCLUSION: Histone methylation was modified during EMT, and combination of epigenetic compounds with conventional or targeted chemotherapy might contribute to reduce metastasis and to enhance clinical responses.

DOT1L as a therapeutic target for the treatment of DNMT3A-mutant acute myeloid leukemia.[Pubmed:27335278]

Blood. 2016 Aug 18;128(7):971-81.

Mutations in DNA methyltransferase 3A (DNMT3A) are common in acute myeloid leukemia and portend a poor prognosis; thus, new therapeutic strategies are needed. The likely mechanism by which DNMT3A loss contributes to leukemogenesis is altered DNA methylation and the attendant gene expression changes; however, our current understanding is incomplete. We observed that murine hematopoietic stem cells (HSCs) in which Dnmt3a had been conditionally deleted markedly overexpress the histone 3 lysine 79 (H3K79) methyltransferase, Dot1l. We demonstrate that Dnmt3a(-/-) HSCs have increased H3K79 methylation relative to wild-type (WT) HSCs, with the greatest increases noted at DNA methylation canyons, which are regions highly enriched for genes dysregulated in leukemia and prone to DNA methylation loss with Dnmt3a deletion. These findings led us to explore DOT1L as a therapeutic target for the treatment of DNMT3A-mutant AML. We show that pharmacologic inhibition of DOT1L resulted in decreased expression of oncogenic canyon-associated genes and led to dose- and time-dependent inhibition of proliferation, induction of apoptosis, cell-cycle arrest, and terminal differentiation in DNMT3A-mutant cell lines in vitro. We show in vivo efficacy of the DOT1L inhibitor EPZ5676 in a nude rat xenograft model of DNMT3A-mutant AML. DOT1L inhibition was also effective against primary patient DNMT3A-mutant AML samples, reducing colony-forming capacity (CFC) and inducing terminal differentiation in vitro. These studies suggest that DOT1L may play a critical role in DNMT3A-mutant leukemia. With pharmacologic inhibitors of DOT1L already in clinical trials, DOT1L could be an immediately actionable therapeutic target for the treatment of this poor prognosis disease.

Description

Pinometostat (EPZ-5676) is a potent DOT1L histone methyltransferase inhibitor with a Ki of 80 pM.

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