Fedratinib (TG101348)

別名：SAR302503

製品コード：S2736 純度：99.99%

Fedratinib (SAR302503, TG101348) is a selective inhibitor of JAK2 with IC50 of 3 nM in cell-free assays, 35- and 334-fold more selective for JAK2 versus JAK1 and JAK3. Fedratinib also inhibits FMS-like tyrosine kinase 3 (FLT3) and RET (c-RET) with IC50 of 15 nM and 48 nM, respectively. Fedratinib has potential antineoplastic activity. Fedratinib inhibits proliferation and induces apoptosis. Phase 2.

CAS No. 936091-26-8

サイズ	価格(税別)	在庫状況
10mM (1mL in DMSO)	JPY 33000	国内在庫あり
5mg	JPY 22000	国内在庫あり
10mg	JPY 29500	国内在庫あり
50mg	JPY 85500	国内在庫あり
1g	JPY 295500	国内在庫あり

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Fedratinib (TG101348)関連製品

関連ターゲット	JAK1 JAK2 JAK3 Tyk2	もっと見る
関連製品	AZD1480 WP1066 Momelotinib (CYT387) Filgotinib (GLPG0634) AT9283 Gandotinib (LY2784544) TG101209 Cerdulatinib (PRT062070) hydrochloride Pacritinib NVP-BSK805 2HCl WHI-P154 FLLL32 Decernotinib (VX-509) CEP-33779 AZ 960 Cerdulatinib (PRT062070) ZM 39923 HCl XL019 BMS-911543 Curcumol Solcitinib Oclacitinib maleate Pyridone 6 Creatine Ritlecitinib (PF-06651600) Deucravacitinib (BMS-986165) Itacitinib (INCB39110) Peficitinib BD750 WHI-P97 JANEX-1 Brevilin A 1,2,3,4,5,6-Hexabromocyclohexane Brepocitinib (PF-06700841) FM-381 SAR-20347 Selective JAK3 inhibitor 1	もっと見る
関連化合物ライブラリー	Kinase Inhibitor Library FDA-approved Drug Library Natural Product Library Tyrosine Kinase Inhibitor Library JAK/STAT compound library	もっと見る

シグナル伝達経路

JAKシグナル伝達経路

JAK阻害剤の選択性比較

阻害剤	Citation	JAK1	JAK2	JAK3	Tyk2	その他
AZD1480	121		++++
AT9283	34		++++	++++	+++	Aurora B,Aurora A,Abl1 (T315I)
Momelotinib (CYT387)	47	+++	+++	+
WP1066	74		+			STAT3
TG101209	18		+++	+		RET,FLT3
Gandotinib (LY2784544)	23	++	++++	++	++	FLT3,FLT4,FGFR2
NVP-BSK805 2HCl	15	++	++++	+++	+++
AZ 960	10		++++
CEP-33779	11		++++
Pacritinib	18		++	+	++	FLT3 (D835Y),FLT3
WHI-P154	11			+		EGFR,Src,VEGFR
BIO	36			+	++	GSK-3,CDK5/p35,CDK2/CyclinA
XL019	7	+	++++	+		PDGFRβ,FLT3
ZM 39923 HCl	6	+		+		TGM2,EGFR
Oclacitinib	1	+++
Ilginatinib hydrochloride	0	++	++++	++
RGB-286638 free base	0		++			cyclin T1-CDK9,cyclin B1-CDK1,GSK-3β
Pyridone 6	3		++++	+++	++++
Cerdulatinib (PRT062070)	6	+++	+++	+++
Ropsacitinib (PF-06826647)	0	+	++		+++
Delgocitinib (JTE-052)	0	++++	++++	+++	++
SAR-20347	1	++	++	++	++++	IFN-α,IL-12
TG-89	0		+
GDC046	0	+	++	+	+++
Deucravacitinib (BMS-986165)	6				++++
WHI-P258	0			+
Selective JAK3 inhibitor 1	1	+	+	++++
Brepocitinib (PF-06700841)	1	+++	+		++
Solcitinib	7	+++
JANEX-1	3			+
Ritlecitinib (PF-06651600)	4			++
FM-381	1			++++
Oclacitinib maleate	6	+++	+++	+	+
Decernotinib (VX-509)	11	+++	+++	++++	+++
Cerdulatinib (PRT062070) hydrochloride	18	+++	+++	+++	++++	MST1,ARK5,Fms
Filgotinib (GLPG0634)	45	+++	++	+	+
FLLL32	13		+
BMS-911543	6		++++	++	++	SET-2
Zotiraciclib	0		++			CDK9,CDK2,CDK1
AG-490	132		✔			EGFR
Zasocitinib	0				✔
G5-7	0		✔
Ginsenoside Rh4	0		✔
cucurbitacin E	0		✔			STAT3
Ivarmacitinib	0	✔
Cucurbitacin I	0		✔
SC99	0		✔
Brevilin A	1		✔			STAT3
Nicotiflorin (Kaempferol-3-O-rutinoside)	0		✔			Bcl-2,Bax,caspase-3
Licochalcone D	0		✔			PARP,Caspase,Met
BD750	2			✔		STAT5,human T-cell proliferation,mouse T-cell proliferation
Ginkgolic acid C17:1	0		✔			PTEN,STAT3,Src
Gusacitinib (ASN-002)	0		✔
RO495	0				✔
NSC 42834	0		✔
1,2,3,4,5,6-Hexabromocyclohexane	1		✔
WHI-P97	1			✔
Creatine	3		✔
Itacitinib (INCB39110)	8	✔
Peficitinib	3		✔
GLPG0634 analogue	0		✔
Go6976	37		✔			FLT3,PKCα,PKCβ1
Curcumol	6		✔

1. "+" indicates inhibitory effect. Increased inhibition is marked by a higher "+" designation. 2. "✔" indicates inhibitory effect, but without specific value.

Cell Data

Cell Lines	Assay Type	Concentration	Incubation Time	活性情報	PMID
HDLM2	Function Assay	0-5 μM	24 h	inhibits JAK2/STAT signaling	24610827
SUPHD1	Function Assay	0-5 μM	24 h	inhibits JAK2/STAT signaling	24610827
L1236	Function Assay	0-5 μM	24 h	inhibits JAK2/STAT signaling	24610827
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生物活性

製品説明

Targets

JAK2 ^[1] (Cell-free assay)	JAK2 (V617F) ^[1] (Cell-free assay)	FLT3 ^[1] (Cell-free assay)	RET ^[1] (Cell-free assay)
3 nM	3 nM	15 nM	48 nM

In Vitro
In vitro	TG-101348 also significantly inhibits JAK2 V617F, Flt3, and Ret with IC50 of 3 nM, 15 nM, and 48 nM, respectively. TG101348 has an IC50 ~300-fold higher for the closely related JAK3 and is a less potent inhibitor of the JAK1 and TYK2 family members. TG101348 inhibits proliferation of a human erythroblast leukemia (HEL) cell line that harbors the JAK2V617F mutation, as well as a murine pro-B cell line expressing human JAK2V617F (Ba/F3 JAK2V617F), with IC50 of 305 nM and 270 nM, respectively. TG-101348 also inhibits proliferation of parental Ba/F3 cells to a comparable level, with IC50 of ~420 nM. TG101348 treatment reduces STAT5 phosphorylation at concentrations that parallel the concentrations required to inhibit cell proliferation. TG101348 induces apoptosis in both HEL and Ba/F3 JAK2V617F cells in a dose-dependent manner. TG101348 does not show proapoptotic activity in control normal human dermal fibroblasts at concentrations up to 10 μM, and the antiproliferative IC50 against fibroblasts is >5 μM. ^[1] TG101348 treatment decreases GATA-1 expression, which is associated with erythroid-skewing of JAK2V617F⁺ progenitor differentiation, and inhibits STAT5 as well as GATA S310 phosphorylation. ^[2] TG101348 inhibits the proliferation of HMC-1.1 (KITV560G) cells, with somewhat lower potency than HMC-1.2 (KITD816V, KITV560G) cells, with IC50 of 740 nM and 407 nM, respectively. ^[3]
Kinase Assay	Cell-free Kinase Activity Assays
Kinase Assay	IC50 values for TG101348 are determined commercially using the InVitrogen kinase profiling service for a 223 kinase screen that included JAK2 and JAK2V617F or Carna Biosciences for the screen of all Janus kinase family members including JAK1 and Tyk2. ATP concentration is set to approximately the Km value for each kinase.
細胞実験	細胞株	EpoBa/F3 JAK2V617F, Ba/F3p210, HEL, and K562
	濃度	Dissolved in DMSO, final concentrations ~10 μM
	反応時間	72 hours
	実験の流れ	Approximately 2 × 10³ cells are plated into microtiter-plate wells in 100 μL RPMI-1640 growth media with indicated concentrations of inhibitor. Following 72 hours incubation with TG101348, 50 μL of XTT dye are added to each well and incubated for 4 hours in a CO₂ incubator. The colored formazan product is measured by spectrophotometry at 450 nm with correction at 650 nm. The concentration in which 50% of the effect (i.e., inhibition of proliferation) is observed (IC50) is determined using the GraphPad Prism 4.0 software. All experiments are performed in triplicate, and the results are normalized to growth of untreated cells. Induction of apoptosis of EpoBa/F3 JAK2V617F, Ba/F3p210, HEL, and K562 cells is determined by DNA fragmentation with DMSO and increasing concentrations of TG101348.
実験結果図	Methods	Biomarkers	結果図	PMID
	Western blot	c-Myc / PIM1 p-JAK2 / p-STAT1 / p-STAT3 / p-STAT6 / p-STAT5 / JAK2		24610827
	Growth inhibition assay	Cell proliferation		24610827

In Vivo
In Vivo	TG101348 has potential for efficacious treatment of JAK2V617F-associated myeloproliferative diseases (MPD). In treated animals, there is a statistically significant reduction in hematocrit and leukocyte count, a dose-dependent reduction/elimination of extramedullary hematopoiesis, and, at least in some instances, evidence for attenuation of myelofibrosis, correlated with surrogate endpoints, including reduction/elimination of JAK2V617F disease burden, suppression of endogenous erythroid colony formation, and in vivo inhibition of JAK-STAT signal transduction. There are no apparent toxicities and no effect on T cell number. ^[1] Oral administration of TG101348 (120 mg/kg) significantly inhibits PV progenitor erythroid differentiation in vivo. ^[2]
動物実験	動物モデル	C57BL/6 mice injected intravenously with whole bone marrow expressing JAK2V617F
	投与量	~120 mg/kg
	投与経路	Oral gavage twice daily (b.i.d.)

NCT Number	Recruitment	Conditions	Sponsor/Collaborators	Start Date	Phases
臨床試験 (data from https://clinicaltrials.gov, updated on 2024-05-22)
NCT04955938	Recruiting	IDH Mutation\|IDH1 Mutation\|IDH2 Gene Mutation\|Blood Cancer\|Myeloproliferative Neoplasm	University of Chicago	October 29 2021	Phase 1
NCT05051553	Completed	Healthy Volunteers	Bristol-Myers Squibb	September 21 2021	Phase 1
NCT04702464	Completed	Healthy Volunteers	Celgene\|Impact Biomedicines Inc. a wholly owned subsidiary of Celgene Corporation	January 12 2021	Phase 1
NCT03983161	Completed	Healthy Volunteers\|Hepatic Impairment	Celgene\|Impact Biomedicines Inc. a wholly owned subsidiary of Celgene Corporation	September 4 2019	Phase 1
NCT03983239	Completed	Healthy Volunteers	Celgene\|Impact Biomedicines Inc. a wholly owned subsidiary of Celgene Corporation	June 21 2019	Phase 1

参考
[1] Wernig G, et al. Cancer Cell, 2008, 13(4), 311-320. [2] Geron I, et al. Cancer Cell, 2008, 13(4), 321-330. [3] Lasho T, et al. Leukemia, 2010, 24(7), 1378-1380.

参考

化学情報

分子量	524.68	化学式	C₂₇H₃₆N₆O₃S
CAS No.	936091-26-8	SDF	Download Fedratinib (TG101348) SDFをダウンロードする
Smiles	CC1=CN=C(N=C1NC2=CC(=CC=C2)S(=O)(=O)NC(C)(C)C)NC3=CC=C(C=C3)OCCN4CCCC4
保管	3年-20°C粉	溶液の保管冷凍と解凍の繰り返しを避けるため小分けにしてください	1年-80°Cin solvent
保管	3年-20°C粉	溶液の保管冷凍と解凍の繰り返しを避けるため小分けにしてください	１ケ月-20°Cin solvent

In vitro
Batch:

DMSO : 100 mg/mL ( (190.59 mM)；吸湿したDMSOは溶解度を減少させます。新しいDMSOをご使用ください。)

Water : Insoluble

Ethanol : Insoluble

モル濃度計算器

in vivo
Batch:

Add solvents to the product individually and in order.

投与溶液組成計算機

Clear solution

5%DMSO 1 40%PEG300 Click to order 2 5%Tween 80 Click to order 3 50%ddH2O

4.0mg/ml (7.62mM)

Taking the 1 mL working solution as an example, add 50 μL of 80 mg/ml clarified DMSO stock solution to 400 μL of PEG300, mix evenly to clarify it; add 50 μL of Tween80 to the above system, mix evenly to clarify; then continue to add 500 μL of ddH2O to adjust the volume to 1 mL. The mixed solution should be used immediately for optimal results.

実験計算

モル濃度計算器

質量	濃度	体積	分子量
=	×	×

希釈計算器分子量計算器

投与溶液組成計算機(クリア溶液)

ステップ１：実験データを入力してください。（実験操作によるロスを考慮し、動物数を1匹分多くして計算・調製することを推奨します）

投与量 mg/kg 動物平均体重 g 投与体積（動物毎）μL 動物数匹

ステップ２：投与溶媒の組成を入力してください。（ロット毎に適した溶解組成が異なる場合があります。詳細については弊社までお問い合わせください）

% DMSO + % + % Tween 80 + % ddH₂O

%DMSO+ %

計算結果：

投与溶媒濃度： mg/ml;

DMSOストック溶液調製方法： mg 試薬を μL DMSOに溶解する（濃度 mg/mL, 注：濃度が当該ロットのDMSO溶解度を超える場合はご連絡ください。 )

投与溶媒調製方法：Take μL DMSOストック溶液に μL PEG300，を加え、完全溶解後μL Tween 80，を加えて完全溶解させた後 μL ddH₂O，を加え完全に溶解させます。

投与溶媒調製方法：μL DMSOストック溶液に μL Corn oil，を加え、完全溶解。

注意：１.ストック溶液に沈殿、混濁などがないことをご確認ください；
２.順番通りに溶剤を加えてください。次のステップに進む前に溶液に沈殿、混濁などがないことを確認してから加えてください。ボルテックス、ソニケーション、水浴加熱など物理的な方法で溶解を早めることは可能です。

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