GNF-5837

製品コードS7519 バッチS751901

化学情報

	Synonyms	N/A	Storage (From the date of receipt)	3 years -20°C powder 1 years -80°C in solvent
	化学式	C₂₈H₂₁F₄N₅O₂
	分子量	535.49	CAS No.	1033769-28-6
Solubility (25°C)*	体外	DMSO	100 mg/mL (186.74 mM)
		Ethanol	9 mg/mL warmed with 50ºC water bath (16.8 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	GNF-5837 is a selective, and orally bioavailable pan-TRK inhibitor for TrkA, and TrkB with IC50 of 8 nM, and 12 nM, respectively.
in vitro	In Ba/F3 cells overexpressing the constitutively active Tel-TRKC fusion, GNF-5837 shows potent anti-Trk activity and potent antiproliferation activity with IC50 of 0.042 μM. ^[1]
in vivo	In both male Balb/c mice and Sprague–Dawley rats, GNF-5837 has the low drug clearance, and moderate biovailability. In mice bearing Rie xenografts expressing TrkA and NGF, GNF-5837 (100 mg/kg/d p.o.) significantly inhibits tumor growth. ^[1]

プロトコル(参考用のみ)

キナーゼアッセイ	Inhibition of biochemical TrkA, TrkB and TrkC
キナーゼアッセイ	TrkA and TrkC biochemical assays are carried out by HTRF method. The reaction mixtures contains 1 μM peptide substrate, 1 μM ATP, and either 1.8 nM TrkA or 34 nM TrkC in the reaction buffer (50mM HEPES pH 7.1, 10mM MgCl₂, 2 mM MnCl₂, 0.01% BSA, 2.5 mM DTT and 0.1 mM Na₃VO₄) at a final volume of 10 μL. All reactions are carried out at room temperature in white ProxiPlate™ 384-well Plus plates and are quenched with 5 μL of 0.2mM EDTA at 60 min. Five μL of the detection reagents (2.5 ng PT66K and 0.05 μg SAXL per well) are added, the plates are incubated at room temperature for 1 h and then read in EnVision reader. Compounds are diluted into assay mixture (final DMSO 0.5%), and IC50 values are determined by 12-point (from 50 to 0.000282 μΜ) inhibition curves in duplicate under the assay conditions. TrkB biochemical assay is carried out by caliper microfluidic method. The reaction mixtures contained 1 μM peptide substrate, 10 μM ATP, and 2 nM TrkB in a reaction buffer containing 100 mM HEPES, pH 7.5, 5 mM MgCl₂, 0.01% Triton X-100, 0.1% BSA, 1 mM DTT, 10 μΜNa₃VO₄, and 10 μΜBeta-Glycerophosphate. The reactions are carried out at room temperature for 3 hrs, and the products are determined by Caliper EZ-reader. Compounds are diluted into assay mixture (final DMSO 1%), and IC50 values are determined by 12-point (from 50 to 0.000282 μΜ) inhibition curves in duplicate under the assay conditions.
細胞アッセイ	細胞株	Wt Ba/F3 cells and Ba/F3 cells transformed with constitutively expressed luciferase reporter and BCR-ABL or Tel-KDR or other Tel fusion kinases
	濃度	~10 μΜ
	反応時間	48 hours
	実験の流れ	Compounds are tested for their ability to inhibit the proliferation of wt Ba/F3 cells and Ba/F3 cells transformed with constitutively expressed luciferase reporter and BCR-ABL or Tel-KDR or other Tel fusion kinases. Parental Ba/F3 cells are maintained in media containing recombinant mouse IL3 and the kinase transformed Ba/F3 cells are maintained in media without IL-3. 7.5 nL of compounds are spotted to each well of 1536-well assay plates by Liquid handling System Echo 555 (Labcyte). 700 cells are then plated into each well of the assay plates in 7 μL culture media per well and compounds are tested at 0.17 nM to 10 uM in 3-fold serial dilutions. The cells were then incubated for 48 hours at 37 °C. 3 μL of Bright-Glo® is added to each well and the plates are read using ViewLux.
動物実験	動物モデル	Mice bearing Rie xenografts expressing TrkA and NGF.
	投薬量	100 mg/kg/d
	投与方法	p.o.

参考

[1] Albaugh P, et al. ACS Med Chem Lett. 2012, 3(2), 140-145.

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：

EGFR-phosphorylated GDH1 harmonizes with RSK2 to drive CREB activation and tumor metastasis in EGFR-activated lung cancer [ Cell Rep, 2022, 41(11):111827]	PubMed: 36516759
Nerve growth factor orchestrates NGAL and matrix metalloproteinases activity to promote colorectal cancer metastasis [ Clin Transl Oncol, 2021, 10.1007/s12094-021-02666-x]	PubMed: 34255268
Trk inhibitor GNF‑5837 suppresses the tumor growth, survival and migration of renal cell carcinoma [ Oncol Rep, 2019, 42(5):2039-2048]	PubMed: 31485624
MAST1 Drives Cisplatin Resistance in Human Cancers by Rewiring cRaf-Independent MEK Activation [ Cancer Cell, 2018, 34(2):315-330]	PubMed: 30033091
Expression of brain-derived neurotrophic factor and its receptor TrkB is associated with poor prognosis and a malignant phenotype in small cell lung cancer. [ Lung Cancer, 2018, 120:98-107]	PubMed: 29748024
Silibinin exerts antidepressant effects by improving neurogenesis through BDNF/TrkB pathway [ Behav Brain Res, 2018, 348:184-191]	PubMed: 29680784

長期の保管のために-20°Cの下で製品を保ってください。

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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