A4166-1ml | EPZ5676 [1380288-87-8] Clinisciences

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.

1. Liu L, Zou J, et al. "Blocking the histone lysine 79 methyltransferase DOT1L alleviates renal fibrosis through inhibition of renal fibroblast activation and epithelial-mesenchymal transition." FASEB J. 2019 Aug 2:fj201801861R. PMID:31373855
2. Kim MS, Cho HI, et al. "JIB-04, A Small Molecule Histone Demethylase Inhibitor, Selectively Targets Colorectal Cancer Stem Cells by Inhibiting the Wnt/β-Catenin Signaling Pathway." Sci Rep. 2018 Apr 26;8(1):6611. PMID:29700375

Physical Appearance	A solid
Storage	Store at -20°C
M.Wt	562.71
Cas No.	1380288-87-8
Formula	C₃₀H₄₂N₈O₃
Solubility	≥28.15 mg/mL in DMSO; insoluble in H2O; ≥50.3 mg/mL in EtOH with ultrasonic
Chemical Name	(2R,3S,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
SDF	Download SDF
Canonical 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
Shipping Condition	Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice.
General tips	We do not recommend long-term storage for the solution, please use it up soon.

Kinase experiment [1]:
Biochemical enzyme inhibition assays	The enzyme inhibition constant (Ki) value for EPZ5676 was determined by fitting inhibition data to the Morrison quadratic equation. Residence time for EPZ5676 was calculated as the reciprocal of the enzymatic-ligand dissociation rate, determined by surface plasmon resonance.
Cell experiment [1]:
Cell lines	MV4-11 cells
Preparation method	The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20 °C for several months.
Reaction Conditions	0.0005 ~ 10 μM; 14 days
Applications	EPZ5676 potently inhibited MV4-11 cell proliferation with an IC50 value of 3.5 nM. Antiproliferative activity was realized after 4 days and was most clear after 7 days of EPZ-5676 treatment.
Animal experiment [1]:
Animal models	Nude rats bearing MV4-11 xenografts
Dosage form	35, 67 or 70 mg/kg/day; i.v.; for 21 days
Applications	In nude rats bearing MV4-11 xenografts, EPZ5676 caused complete tumor regressions that were sustained well beyond the compound infusion period with no significant weight loss or signs of toxicity.
Other notes	Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
References: [1]. 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.

Description	EPZ5676 is a potent and selective inhibitor of DOT1L methyltransferase with Ki value of 80 pM.
Targets	DOT1L
IC50	80 pM (Ki)

Chemical structure

EPZ5676 [1380288-87-8]

Référence A4166-1ml

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