GSK126

製品コードS7061 バッチS706112

化学情報

	Synonyms	GSK2816126A, GSK2816126	Storage (From the date of receipt)	3 years -20°C powder 1 years -80°C in solvent
	化学式	C₃₁H₃₈N₆O₂
	分子量	526.67	CAS No.	1346574-57-9
Solubility (25°C)*	体外	DMSO	16 mg/mL warmed with 50ºC water bath (30.37 mM)
		Ethanol	6 mg/mL warmed with 50ºC water bath (11.39 mM)
		Water	Insoluble
* <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

溶剤液（一定の濃度）を調合する

生物活性

製品説明	GSK126 (GSK2816126A、GSK2816126) は強力で選択性の高い EZH2 メチルトランスフェラーゼ (methyltransferase) 阻害剤(IC50=9.9 nM)であり、EZH2 に対して 20 種類以上の他のヒトメチルトランスフェラーゼよりも 1000 倍以上の選択性を持ちます。
in vitro	In vitro, GSK126 most potently inhibits H3K27me3, followed by H3K27me2 in both EZH2 wild-type and mutant DLBCL cell lines. GSK126 also effectively inhibits the proliferation of EZH2 mutant DLBCL cell lines, and induces transcriptional activation of EZH2 target genes in sensitive cell lines. ^[1] In A687V EZH2-mutant cells, GSK126 treatment results in a global decrease in H3K27me3, robust gene activation, caspase activation, and decreased proliferation. ^[2] In parental H2087 cells, GSK126 inhibits the expression of VEGF-A and phosphorylated Ser(473)-AKT, and thus causes the inhibition of cell proliferation, migration and metastasis. ^[3]
in vivo	In mice bearing KARPAS-422 and Pfeiffer xenografts, GSK126 (150 mg/kg/d, i.p.) decreases global H3K27me3, increases gene expression, and thus causes marked tumour regression. ^[1]

プロトコル(参考用のみ)

キナーゼアッセイ	EZH2 assay
キナーゼアッセイ	The five-member PRC2 complex (Flag–EZH2, EED, SUZ12, AEBP2, RbAp48) containing either wild-type or mutant EZH2 is prepared. GSK126 is dissolved in DMSO and tested at concentrations of 0.6 nM to 300 nM with a final DMSO concentration of 2.5%. In contrast to wild-type EZH2 which prefers H3K27me0 as a substrate in vitro, EZH2 Y641 mutants prefer H3K27me2 and have little activity with H3K27me0 or H3K27me1. The A677G mutant is distinct from both the wild-type and Y641 mutant forms of EZH2 in that it efficiently methylates H3K27me0, H3K27me1, and H3K27me2; therefore, histone H3 peptides (residues 21–44; 10 μM final) with either K27me0 (wild type, A677G EZH2), K27me1 (A677G EZH2), or K27me2 (A677G, Y641N, Y641C, Y641H, Y641S and Y641F EZH2) are used as methyltransferase substrates. GSK126 is added to plates followed by addition of 6 nM EZH2 complex and peptide. As the potency of GSK126 is at or near the tight binding limit of an assay run at [SAM] = Km, IC50 values are measured at a high concentration of the competitive substrate SAM relative to its Km (7.5 μM SAM where the SAM Km is 0.3 μM). Under these conditions, the contribution from the enzyme concentration becomes relatively small and accurate estimates of Ki can be calculated. Reactions are initiated with [³H]-SAM, incubated for 30 min, quenched with the addition of 500-fold excess unlabelled SAM, and the methylated product peptide is captured on phosphocellulose filters according to the vendor supplied protocol for MSPH Multiscreen plates. Plates are read on a TopCount after adding 20 μL of Microscint-20 cocktail. Apparent Ki values are calculated using the Cheng–Prusoff relationship for a competitive inhibitor. IC50=Ki (1+[S]/Km)+[E]/2, where E is the enzyme and S is the substrate.
細胞アッセイ	細胞株	46 lymphoma cell lines
	濃度	0~10 μM
	反応時間	6 days
	実験の流れ	The optimal cell seeding is determined empirically for all cell lines by examining the growth of a wide range of seeding densities in a 384-well format to identify conditions that permitted proliferation for 6 days. Cells are then plated at the optimal seeding density 24 h before treatment (in duplicate) with a 20-point two fold dilution series of GSK126 or 0.15% DMSO. Plates are incubated for 6 days at 37°C in 5% CO₂. Cells are then lysed with CellTiter-Glo (CTG) and chemiluminescent signal is detected with a TECAN Safire2 microplate reader. In addition, an untreated plate of cells is harvested at the time of compound addition (T0) to quantify the starting number of cells. CTG values obtained after the 6 day treatment are expressed as a percent of the T0 value and plotted against compound concentration. Data are fit with a four-parameter equation to generate a concentration response curve and the concentration of GSK126 required to inhibit 50% of growth (growth IC50) is determined.
動物実験	動物モデル	Female beige SCID mice bearing Pfeiffer or KARPAS-422 tumors
	投薬量	150 mg/kg/day
	投与方法	i.p.

参考

カスタマーフィードバック

: , , Br J Haematol, 2017, 178(6):936-948

: Data from [Data independently produced by , , Autophagy, 2015, 11(12):2309-22.]

: Data from [Data independently produced by , , Mol Cancer, 2017, 16(1):22]

Selleckの高級品が、幾つかの出版された研究調査結果（以下を含む）で使われた：

EZH2 inhibitors promote β-like cell regeneration in young and adult type 1 diabetes donors [ Signal Transduct Target Ther, 2024, 9(1):2]	PubMed: 38161208
DNA hypomethylation silences anti-tumor immune genes in early prostate cancer and CTCs [ Cell, 2023, 186(13):2765-2782.e28]	PubMed: 37327786
EZH2 mediated metabolic rewiring promotes tumor growth independently of histone methyltransferase activity in ovarian cancer [ Mol Cancer, 2023, 22(1):85]	PubMed: 37210576
EZH2 inhibition remodels the inflammatory senescence-associated secretory phenotype to potentiate pancreatic cancer immune surveillance [ Nat Cancer, 2023, 4(6):872-892]	PubMed: 37142692
An ATR-PrimPol pathway confers tolerance to oncogenic KRAS-induced and heterochromatin-associated replication stress [ Nat Commun, 2023, 14(1):4991]	PubMed: 37591859
An ATR-PrimPol pathway confers tolerance to oncogenic KRAS-induced and heterochromatin-associated replication stress [ Nat Commun, 2023, 14(1):4991]	PubMed: 37591859
Epigenetic suppression of PGC1α (PPARGC1A) causes collateral sensitivity to HMGCR-inhibitors within BRAF-treatment resistant melanomas [ Nat Commun, 2023, 14(1):3251]	PubMed: 37277330
Genetic screens reveal new targetable vulnerabilities in BAP1-deficient mesothelioma [ Cell Rep Med, 2023, S2666-3791(22)00494-3]	PubMed: 36657447
CUL4B-DDB1-COP1-mediated UTX downregulation promotes colorectal cancer progression [ Exp Hematol Oncol, 2023, 12(1):77]	PubMed: 37679762
Targeting polycomb repressor complex 2-mediated bivalent promoter epigenetic silencing of secreted frizzled-related protein 1 inhibits cholangiocarcinoma progression [ Clin Transl Med, 2023, 13(12):e1502]	PubMed: 38050190

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人間や獣医の診断であるか治療的な使用のためにでない。

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