Home JAK/STAT JAK inhibitor Fedratinib (TG101348)

연구용

Fedratinib (TG101348) JAK2 Inhibitor

제품 번호: S2736

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.
Fedratinib (TG101348) JAK inhibitor Chemical Structure

화학 구조

분자량: 524.68

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품질 관리 (Quality Control)

배치: 순도: 99.99%
99.99

함께 자주 사용되는 제품 Fedratinib (TG101348)

Momelotinib (CYT387)

This compound and Momelotinib are new JAK inhibitors being tested for managing myeloproliferative neoplasms.

세포 배양, 처리 및 작업 농도
(Cell Culture, Treatment & Working Concentration)

세포주 분석 유형 농도 배양 시간 제형 활성 설명 PMID
H1975 Apoptosis Assay 0.5-2 μM 12-48 h DMSO induces apoptosis in both dose- and time- dependent manner 25869210
H1650 Apoptosis Assay 0.5-2 μM 12-48 h DMSO induces apoptosis in both dose- and time- dependent manner 25869210
H1975 Function Assay 0.25-1 μM 24 h DMSO inhibits expression of apoptosis-related protein Bcl-XL, Bcl-2, survivin, XIAP 25869210
H1650 Function Assay 0.25-1 μM 24 h DMSO inhibits expression of apoptosis-related protein Bcl-XL, Bcl-2, survivin, XIAP 25869210
H1975 Growth Inhibition Assay 1 μM 48 h DMSO sensitizes cells to the cytotoxicity of erlotinib 25869210
H1650 Growth Inhibition Assay 1 μM 48 h DMSO sensitizes cells to the cytotoxicity of erlotinib 25869210
CD4+ T Function Assay 0.01-1 μM 48 h DMSO reduces the phosphorylation levels of JAK2 and STAT3  25572535
Caco-2  Function Assay 0-120 μM 7 min inhibits thiamine uptake with an IC50 of 2.1 µM 25063672
Caco-2  Function Assay 10/50/100 μM 2 h decreases the flux of [3H]thiamine across the monolayer with IC50 of 6.5 μM 25063672
HEK293 MSR  Function Assay 0-10 μM 7 min inhibits hTHTR2 with an IC50 of 1.2 µM 25063672
MedB-1 Function Assay 1/2 μM 24 h decreases STAT6 phosphorylation concentration dependently 24977668
U2940 Function Assay 1/2 μM 24 h decreases STAT6 phosphorylation concentration dependently 24977668
K1106 Function Assay 1/2 μM 24 h decreases STAT6 phosphorylation concentration dependently 24977668
K562 Growth Inhibition Assay 0-1 μM 72 h inhibits K562 cell proliferation at high concentration 24775308
MDA-MB-468  Growth Inhibition Assay 3 µM 48 h enhanced sibcl6 induced loss of cell viability  24662818
MDA-MB-468 Growth Inhibition Assay 0-4 μM 48 h results significant loss of viability compared to RI-BPI alone 24662818
L428 Growth Inhibition Assay 0-5 μM 48 h inhibits cell growth significantly 24610827
KMH2 Growth Inhibition Assay 0-5 μM 48 h inhibits cell growth significantly 24610827
L1236 Growth Inhibition Assay 0-5 μM 48 h inhibits cell growth significantly 24610827
SUPHD1 Growth Inhibition Assay 0-5 μM 48 h inhibits cell growth significantly 24610827
HDLM2 Growth Inhibition Assay 0-5 μM 48 h inhibits cell growth significantly 24610827
K1106P Growth Inhibition Assay 0-5 μM 48 h inhibits cell growth significantly 24610827
L428 Apoptosis Assay 0/0.625/1.25 μM 48 h induces the apoptosis  24610827
KMH2 Apoptosis Assay 0/0.625/1.25 μM 48 h induces the apoptosis  24610827
L1236 Apoptosis Assay 0/0.625/1.25 μM 48 h induces the apoptosis  24610827
SUPHD1 Apoptosis Assay 0/0.625/1.25 μM 48 h induces the apoptosis  24610827
HDLM2 Apoptosis Assay 0/0.625/1.25 μM 48 h induces the apoptosis  24610827
K1106P Apoptosis Assay 0/0.625/1.25 μM 48 h induces the apoptosis  24610827
L428 Function Assay 0-5 μM 24 h inhibits JAK2/STAT signaling 24610827
KMH2 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
SUPHD1 Function Assay 0-5 μM 24 h inhibits JAK2/STAT signaling 24610827
HDLM2 Function Assay 0-5 μM 24 h inhibits JAK2/STAT signaling 24610827
K1106P Function Assay 0-5 μM 24 h inhibits JAK2/STAT signaling 24610827
MM.1S  Growth Inhibition Assay IC50=1-3 μM 24584101
TpoR JAK2 WT Growth Inhibition Assay IC50=1.4 (1.3–1.5) μM 24251790
TpoR JAK2 V617F Growth Inhibition Assay IC50=0.8 (0.7–0.9) μM 24251790
TpoR W515L Growth Inhibition Assay IC50=0.8 (0.7–1.0) μM 24251790
Bcr-abl Growth Inhibition Assay IC50=2.7 (2.2–3.3) μM 24251790
JAK2 TW Growth Inhibition Assay IC50=1.8 (1.5–2.3) μM 24251790
JAK2 V617F Growth Inhibition Assay IC50=0.6 (0.6–0.7) μM 24251790
MedB-1 Growth Inhibition Assay 4 μM 24/48/72 h DMSO inhibits cell growth time dependently 23852366
K1106 Growth Inhibition Assay 4 μM 24/48/72 h DMSO inhibits cell growth time dependently 23852366
U2940 Growth Inhibition Assay 4 μM 24/48/72 h DMSO inhibits cell growth time dependently 23852366
FE-PD Growth Inhibition Assay 0.063-4 μM IC50=9.5 μM, inhibits cell growth dose dependently 23372669
HEL Growth Inhibition Assay 0.063-4 μM IC50=1.5 μM, inhibits cell growth dose dependently 23372669
K-562 Growth Inhibition Assay 0.063-4 μM IC50=2.5 μM, inhibits cell growth dose dependently 23372669
L-82 Growth Inhibition Assay 0.063-4 μM IC50=0.98 μM, inhibits cell growth dose dependently 23372669
MAC-1 Growth Inhibition Assay 0.063-4 μM IC50=0.52 μM, inhibits cell growth dose dependently 23372669
MAC-2A Growth Inhibition Assay 0.063-4 μM IC50=0.69 μM, inhibits cell growth dose dependently 23372669
MAC-2B Growth Inhibition Assay 0.063-4 μM IC50=0.54 μM, inhibits cell growth dose dependently 23372669
MY-LA Growth Inhibition Assay 0.063-4 μM IC50=2.1 μM, inhibits cell growth dose dependently 23372669
NC-NC Growth Inhibition Assay 0.063-4 μM IC50=1.0 μM, inhibits cell growth dose dependently 23372669
SE-AX Growth Inhibition Assay 0.063-4 μM IC50=1.5 μM, inhibits cell growth dose dependently 23372669
SR-786 Growth Inhibition Assay 0.063-4 μM IC50=4.6 μM, inhibits cell growth dose dependently 23372669
M-MOK  Growth Inhibition Assay 25 µM  24/48/72 h DMSO inhibits cell growth time dependently 21853157
HEL Growth Inhibition Assay IC50=305 nM 18394554
Ba/F3 JAK2V617F Growth Inhibition Assay IC50=270 nM 18394554
MV4-11 Antiproliferative assay 72 hrs Antiproliferative activity against human MV4-11 cells after 72 hrs by celltiter-blue assay, EC50 = 0.079 μM. 28280261
MM1S Antiproliferative assay 72 hrs Antiproliferative activity against human MM1S cells after 72 hrs by trypan blue exclusion assay, IC50 = 1 μM. 28280261
NB1643 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB1643 cells 29435139
SK-N-MC qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-MC cells 29435139
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화학 정보, 보관 및 안정성 (Chemical Information, Storage & Stability)

분자량 524.68 화학식

C27H36N6O3S

 보관 (수령일로부터)
CAS 번호 936091-26-8 SDF 다운로드 원액 보관

동의어 SAR302503 Smiles CC1=CN=C(N=C1NC2=CC(=CC=C2)S(=O)(=O)NC(C)(C)C)NC3=CC=C(C=C3)OCCN4CCCC4

용해도 (Solubility)

In vitro
배치:

DMSO : 100 mg/mL (190.59 mM)
(수분으로 오염된 DMSO는 용해도를 감소시킬 수 있습니다. 신선하고 무수 DMSO를 사용하십시오.)

Water : Insoluble

Ethanol : Insoluble

몰농도 계산기

질량 농도 부피 분자량
희석 계산기 분자량 계산기

In vivo
배치:

생체 내 제형 계산기 (투명한 용액)

1단계: 아래 정보 입력 (권장: 실험 중 손실을 고려하여 추가 동물 포함)

mg/kg g μL

2단계: 생체 내 제형 입력 (이것은 계산기일 뿐 제형이 아닙니다. 용해도 섹션에 생체 내 제형이 없는 경우 먼저 당사에 문의하십시오.)

% DMSO % % Tween 80 % ddH2O
%DMSO %

계산 결과:

작업 농도: mg/ml;

DMSO 원액 준비 방법: mg 약물 사전 용해 μL DMSO ( 원액 농도 mg/mL, 농도가 해당 약물 배치의 DMSO 용해도를 초과하는 경우 먼저 당사에 문의하십시오. )

생체 내 제형 준비 방법: 취하다 μL DMSO 원액, 다음 추가μL PEG300, 혼합하고 투명하게 한 다음 추가μL Tween 80, 혼합하고 투명하게 한 다음 추가 μL ddH2O, 혼합하고 투명하게 합니다.

생체 내 제형 준비 방법: 취하다 μL DMSO 원액, 다음 추가 μL 옥수수 기름, 혼합하고 투명하게 합니다.

참고: 1. 다음 용매를 추가하기 전에 액체가 투명한지 확인하십시오.
2. 용매를 순서대로 추가해야 합니다. 다음 용매를 추가하기 전에 이전 추가에서 얻은 용액이 투명한 용액인지 확인해야 합니다. 와동, 초음파 또는 뜨거운 물 중탕과 같은 물리적 방법을 사용하여 용해를 도울 수 있습니다.

작용 메커니즘 (Mechanism of Action)

Targets/IC50/Ki
JAK2
(Cell-free assay)
3 nM
JAK2 (V617F)
(Cell-free assay)
3 nM
FLT3
(Cell-free assay)
15 nM
RET
(Cell-free assay)
48 nM
시험관 내(In vitro)

Fedratinib (TG101348) significantly inhibits JAK2 V617F, Flt3, and Ret with IC50 of 3 nM, 15 nM, and 48 nM, respectively. This compound has an IC50 ~300-fold higher for the closely related JAK3 and is a less potent inhibitor of the JAK1 and TYK2 family members. It 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. Its 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. It 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. This compound treatment decreases GATA-1 expression, which is associated with erythroid-skewing of JAK2V617F+ progenitor differentiation, and inhibits STAT5 as well as GATA S310 phosphorylation. 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.

키나아제 분석
Cell-free Kinase Activity Assays
Fedratinib (TG101348) IC50 값은 JAK2 및 JAK2V617F를 포함하는 223개 키나아제 스크리닝을 위한 InVitrogen 키나아제 프로파일링 서비스 또는 JAK1 및 Tyk2를 포함한 모든 Janus kinase 계열 구성원을 스크리닝하기 위해 Carna Biosciences를 사용하여 상업적으로 결정됩니다. ATP 농도는 각 키나아제에 대한 Km 값과 거의 동일하게 설정됩니다.
생체 내(In vivo)

Fedratinib (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. Oral administration of this compound (120 mg/kg) significantly inhibits PV progenitor erythroid differentiation in vivo.

참조

적용 분야 (Applications)

방법 바이오마커 이미지 PMID
Western blot p-JAK2 / p-STAT1 / p-STAT3 / p-STAT6 / p-STAT5 / JAK2 c-Myc / PIM1
S2736-WB1
24610827
Growth inhibition assay Cell proliferation
S2736-viability1
24610827

임상시험 정보 (Clinical Trial Information)

(데이터 출처 https://clinicaltrials.gov, 업데이트 날짜 2024-05-22)

NCT 번호 모집 조건 스폰서/협력자 시작일 단계
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