Laduviglusib (CHIR-99021) HCl

製品コードS2924 バッチS292410

化学情報

	Synonyms	CT99021 HCl	Storage (From the date of receipt)	3 years -20°C powder 1 years -80°C in solvent
	化学式	C₂₂H₁₈Cl₂N_8.HCl
	分子量	501.8	CAS No.	1797989-42-4
Solubility (25°C)*	体外	DMSO	100 mg/mL (199.28 mM)
		Ethanol	6 mg/mL (11.95 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	ラドゥビグルシブ塩酸塩 (Laduviglusib (CHIR-99021; CT99021) HCl) は CHIR-99021 の塩酸塩で、GSK-3α/β 阻害剤 (IC50 = 10 nM/6.7 nM) です。 CHIR-99021 は、最も近縁なホモログである Cdc2 および ERK2 と比較して、GSK-3 に対して 500 倍を超える選択性を示します。 CHIR-99021 は、Wnt/β-カテニンシグナル伝達経路の強力な薬理学的活性化因子です。 CHIR-99021 は、光誘発されるオートファジー (autophagy) を大幅にレスキューし、GR、RORα、およびオートファジー関連タンパク質量を増大します。
in vitro	CHIR-99021 shows greater than 500-fold selectivity for GSK-3 versus its closest homologs CDC2 and ERK2, as well as other protein kinases. Furthermore, CHIR-99021 shows only weak binding to a panel of 22 pharmacologically relevant receptors and little inhibitory activity against a panel of 23 nonkinase enzymes. CHIR-99021 induces the activation of glycogen synthase (GS) in insulin receptor-expressing CHO-IR cells with EC50 of 0.763 μM. ^[1] In addition to simulating the actions of insulin, inhibition of GSK-3 by CHIR-99021 (3 μM) increases free cytosolic β-catenin by 1.9-fold, mimicking the canonical Wnt signaling pathway in 3T3-L1 preadipocytes. During any of the first 3 days of differentiation, CHIR-99021 treatment inhibits the preadipocyte differentiation with IC50 of 0.3 μM by blocking induction of CCAAT/enhancer-binding protein α (C/EBPα) and peroxisome proliferator-activated receptor γ (PPARγ). ^[2] Unlike lithium chloride and AR-A014418, CHIR-99021 treatment does not reduce the viability of INS-1E cells even at high concentrations. Instead, CHIR-99021 robustly increases the rate of proliferation of INS-1E cells in a dose-dependent manner, and significantly inhibits INS-E cell death induced by high glucose and high palmitate in a concentration-dependent manner. CHIR-99021 promotes primary beta cell replication in isolated rat islets at concentrations as low as 1 μM, with 2-3 fold increase of cell replication at 5 μM of CHIR-99021 treatment. ^[3]
in vivo	Oral administration of CHIR-99021 at 30 mg/kg enhances glucose metabolism in a rodent model of type 2 diabetes, with a maximal plasma glucose reduction of nearly 150 mg/dl 3-4 hours after administration, while plasma insulin remains at or below control levels. Oral administration of CHIR-99021 at 16 or 48 mg/kg 1 hour before oral glucose challenges in ZDF rats significantly improves glucose tolerance with 14% and 33% reduction in plasma glucose at 16 mg/kg and 48 mg/kg, respectively, and the higher dose of CHIR-99021 also reduces hyperglycemia before the oral glucose challenge. ^[1]

プロトコル(参考用のみ)

キナーゼアッセイ	Cell-free kinase assays
キナーゼアッセイ	Polypropylene 96-well plates are filled with 300 μL/well buffer (50 mM tris HCl, 10 mM MgCl₂, 1 mM EGTA, 1 mM dithiothreitol, 25 mM β-glycerophosphate, 1 mM NaF, 0.01% BSA, pH 7.5) containing 27 nM GSK-3α or 29 nM GSK-3β, and 0.5 μM biotin-CREB peptide substrate. Various concentrations of CHIR-99021 are added in 3.5 μL of DMSO, followed by 50 μL of ATP stock to yield a final concentration of 1 μM ATP in all cell-free assays. After incubation, triplicate 100-μL aliquots are transferred to Combiplate eight plates containing 100 μL/well 50 μM ATP and 20 mM EDTA. After 1 hour, the wells are rinsed five times with PBS, filled with 200 μL of scintillation fluid, sealed, left 30 minutes, and counted in a scintillation counter. All steps are performed at room temperature.
細胞アッセイ	細胞株	INS-1E
	濃度	Dissolved in DMSO, final concentrations ~ 20 μM
	反応時間	1, or 4 days
	実験の流れ	Cells are maintained for 24 hours in starvation medium (culture medium with only 5 mM glucose, 1% fetal calf serum). Then cells are exposed to various concentrations of CHIR-99021 for 1, or 4 days. Cell number is measured by staining of cellular DNA with CyQuant dye, which becomes fluorescent when bound to DNA. Fluorescence is measured after 30 minutes of incubation using the FLUOstar Optima reader. Cell replication is determined by BrdUrd incorporation. BrdUrd labeling solution is added to the medium for the last 4 hours before the cells are fixed using FixDenat solution and incubated with monoclonal anti-BrdUrd-POD antibodies. After substrate solution is added to each well, the light emission is measured in a microplate luminometer using the Analyst HT detection system.
動物実験	動物モデル	Female db/db mice or male ZDF rats with type 2 diabetes
	投薬量	~48 mg/kg
	投与方法	Orally

参考

カスタマーフィードバック

: Data from [Data independently produced by J Biol Chem, 2015, 290(9), 5592-605 ]

: Data from [Proc Natl Acad Sci U S A, 2012, 109(27):E1848-57]

: Data from [Stem Cells, 2012, 30, 1863-1874]

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：

Symbolic recording of signalling and cis-regulatory element activity to DNA [ Nature, 2024, 10.1038/s41586-024-07706-4]	PubMed: 39020177
Symbolic recording of signalling and cis-regulatory element activity to DNA [ Nature, 2024, 632(8027):1073-1081]	PubMed: 39020177
DNA-guided transcription factor cooperativity shapes face and limb mesenchyme [ Cell, 2024, 187(3):692-711.e26]	PubMed: 38262408
DNA-guided transcription factor cooperativity shapes face and limb mesenchyme [ Cell, 2024, 187(3):692-711.e26]	PubMed: 38262408
Directed Differentiation of Human Induced Pluripotent Stem Cells to Heart Valve Cells [ Circulation, 2024, 149(18):1435-1456]	PubMed: 38357822
Preclinical efficacy and safety of encapsulated proliferating human hepatocyte organoids in treating liver failure [ Cell Stem Cell, 2024, S1934-5909(24)00048-1]	PubMed: 38458193
Lung endothelium exploits susceptible tumor cell states to instruct metastatic latency [ Nat Cancer, 2024, 10.1038/s43018-023-00716-7]	PubMed: 38308117
The transcriptional regulatory network modulating human trophoblast stem cells to extravillous trophoblast differentiation [ Nat Commun, 2024, 15(1):1285]	PubMed: 38346993
The emergence of Sox and POU transcription factors predates the origins of animal stem cells [ Nat Commun, 2024, 15(1):9868]	PubMed: 39543096
Self-renewing human naïve pluripotent stem cells dedifferentiate in 3D culture and form blastoids spontaneously [ Nat Commun, 2024, 15(1):668]	PubMed: 38253551

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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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