5.05052

Ezh2/Ezh1 Inhibitor, UNC1999

• Synonym(e): Ezh2/Ezh1 Inhibitor, UNC1999, Enhancer of Zested Homolog 1 Inhibitor, 1-Isopropyl-6-(6-(4-isopropylpiperazin-1-yl)pyridin-3-yl)-N-((6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl)-1H-indazole-4-carboxamide, Ezh1 Inhibitor, Ezh2 Inhibitor IV, HMTase Inhibitor XII, Histone Lysi, Enhancer of Zested Homolog 1 Inhibitor, 1-Isopropyl-6-(6-(4-isopropylpiperazin-1-yl)pyridin-3-yl)-N-((6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl)-1H-indazole-4-carboxamide, Ezh1 Inhibitor, Ezh2 Inhibitor IV, HMTase Inhibitor XII, Histone Lysin
• Empirische Formel (Hill-System): C₃₃H₄₃N₇O₂
• CAS-Nummer: 1431612-23-5
• Molekulargewicht: 569.74
• UNSPSC-Code: 12352200
• PubChem Substanz-ID: 72551585
• NACRES: NA.77

Eigenschaften

• Assay: ≥98% (HPLC)
• Qualitätsniveau: 100
• Form: powder
• Hersteller/Markenname: Calbiochem^®
• Lagerbedingungen: OK to freeze; protect from light
• Farbe: white
• Löslichkeit: DMSO: 100 mg/mL
• Lagertemp.: 2-8°C
• SMILES String: CCCC1=C(C(=O)NC(=C1)C)CNC(=O)C2=C3C=NN(C3=CC(=C2)C4=CN=C(C=C4)N5CCN(CC5)C(C)C)C(C)C

Beschreibung

Allgemeine Beschreibung

A cell-permeable GSK126 structural analog that acts as a potent, SAM-, but not substrate-, competitive inhibitor against Ezh1 and Ezh2 (IC₅₀ = 5 and 45 nM against PRC2 complex containing Ezh2 or Ezh1 in H3 peptide methylation assays; [SAM] = 5 µM), while exhibiting much reduced or little potency toward panels of 15 other methyltransferases, 50 kinases, as well as 43 GPCRs, transporters, and ion channels, although high affinity binding is observed with Sigma-2 receptor S2R/PGRMC1 (K_i = 65 nM) with unknown impact toward its function. Cellular H3K27me3 level is shown to be largely reduced in MCF10A, MCF7, and DB cells with no significant effect on proliferation upon a 3-day UNC1999 treatment (IC_max = 3 to 5 µM), while complete cell death is reported in the EZH2 Y641N-harboring DB cell line upon an 8-day 5 µM drug exposure. Both its oral bioavailability in mice and enhanced Ezh1 potency can greatly complement the Ezh2-selective GSK126 in in vitro and in vivo studies.

A cell-permeable GSK126 structural analog that acts as a potent, SAM-, but not substrate-, competitive inhibitor against Ezh1 and Ezh2 (IC₅₀ = 5, 20, 20, 45 nM against PRC2 complex containing Ezh2 wt, Ezh2 Y641F, Ezh2 Y641N, or wt Ezh1 in H3 peptide methylation assays; [SAM] = 5 µM), while exhibiting much reduced or little potency toward panels of 15 other methyltransferases (IC₅₀ >10 µM), 50 kinases (≤20% inhibition at 10µM), as well as 43 GPCRs, transporters, and ion channels, although high affinity binding is observed with Sigma-2 receptor S2R/PGRMC1 (K_i = 65 nM) with unknown impact toward its function. Cellular H3K27me3 level is shown to be largely reduced in MCF10A, MCF7, and DB cells with no significant effect on proliferation upon a 3-day UNC1999 treatment (IC_max = 3 to 5 µM), while complete cell death is reported in the EZH2 Y641N-harboring DLBCL line DB cell culture upon an 8-day 5 µM drug exposure. Exhibits good bioavailability in mice with the plasma drug concentration maintained above 100 nM for 20 h and 24 h, respectively, following a single 50 mg/kg oral or i.p. dosage (C_max = 4.7 and >9.7 µM, respectively). Both its oral bioavailability and enhanced Ezh1 potency can greatly complement the Ezh2-selective GSK126 in in vitro and in vivo studies.

Biochem./physiol. Wirkung

Cell permeable: yes

Primary Target
Ezh2

Reversible: yes

Secondary Target
Ezh1

Verpackung

Packaged under inert gas

Warnhinweis

Toxicity: Standard Handling (A)

Rekonstituierung

Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 6 months at -20°C.

Sonstige Hinweise

Konze, K.D., et al. 2013. ACS Chem. Biol.8, 1324.

Rechtliche Hinweise

CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany

Sicherheitshinweise

• Lagerklassenschlüssel: 11 - Combustible Solids
• WGK: WGK 3
• Flammpunkt (°F): Not applicable
• Flammpunkt (°C): Not applicable