Home Angiogenesis FGFR 억제제 AZD4547 (Fexagratinib)

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AZD4547 (Fexagratinib) FGFR 억제제

제품 번호: S2801

Fexagratinib (AZD4547, ABSK 091)은 세포 무함유 분석(cell-free assays)에서 FGFR1/2/3을 표적으로 하며 IC50 값이 각각 0.2 nM/2.5 nM/1.8 nM인 새로운 선택적 FGFR 억제제입니다. FGFR4 및 VEGFR2(KDR)에 대해서는 더 약한 활성을 보이며, IGFR, CDK2, p38에 대해서는 거의 활성을 보이지 않습니다. 임상 2/3상 단계입니다.
AZD4547 (Fexagratinib) FGFR 억제제 Chemical Structure

화학 구조

분자량: 463.57

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품질 관리 (Quality Control)

배치: 순도: 99.96%
99.96

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

세포주 분석 유형 농도 배양 시간 제형 활성 설명 PMID
SNU449 Growth Inhibition Assay 72 h IC50=0.082 μM 26351320
SK-HEP-1 Growth Inhibition Assay 72 h IC50=0.084 μM 26351320
SNU475 Growth Inhibition Assay 72 h IC50=5.4 μM 26351320
Hep3B Growth Inhibition Assay 72 h IC50=6.43 μM 26351320
PLC/PRF5 Growth Inhibition Assay 72 h IC50=6.55 μM 26351320
Hur7 Growth Inhibition Assay 72 h IC50=7.25 μM 26351320
HepG2 Growth Inhibition Assay 72 h IC50=8.73 μM 26351320
SNU449 Clonogenic assay 1 µM 24 h decreases colony formation significantly 26351320
SK-HEP-1 Clonogenic assay 1 µM 24 h decreases colony formation significantly 26351320
SNU449 Function Assay 0-2 μM 48 h causes a decrease of FRS2，AKT, and ERK phosphorylation 26351320
SK-HEP-1 Function Assay 0-2 μM 48 h causes a decrease of FRS2，AKT, and ERK phosphorylation 26351320
BaF3 FLT3-TEL Growth Inhibition Assay GI50=4.6 ± 0.577 μM 26294741
BaF3 RET-TEL Growth Inhibition Assay GI50=0.39 ± 0.048 μM 26294741
BaF3 Parental Growth Inhibition Assay GI50﹥10 μM 26294741
MOLM14 FLT3/ITD Growth Inhibition Assay GI50=0.484 ± 0.157 μM 26294741
MV4-11 FLT3/ITD Growth Inhibition Assay GI50=0.459 ± 0.046 μM 26294741
TT RET C634W Growth Inhibition Assay GI50=2.9 ± 0.904 μM 26294741
AN3-CA FGFR2 N550K, K310R Growth Inhibition Assay GI50=0.031 ± 0.023 μM 26294741
MFE296 FGFR2 N550K Growth Inhibition Assay GI50=0.730 ± 0.057 μM 26294741
MFE280 FGFR2 S252W Growth Inhibition Assay GI50=0.218 ± 0.073 μM 26294741
Ishikawa FGFF2 over exp. Growth Inhibition Assay GI50=4.5 ± 1.51 μM 26294741
HEC1A Normal FGFR2 Growth Inhibition Assay GI50﹥10 μM 26294741
A549 Cell viability Assay 0.1/1 μM 48 h enhances Erlotinib induced viability loss 26053020
SGC-7901 Growth Inhibition Assay 1 nM-10 μM 72 h IC50 of 5-10 μM, inhibits cell viability dose dependently 25576915
HGC-27 Growth Inhibition Assay 1 nM-10 μM 72 h IC50 of 5-10 μM, inhibits cell viability dose dependently 25576915
MKN-28 Growth Inhibition Assay 1 nM-10 μM 72 h IC50 of 5-10 μM, inhibits cell viability dose dependently 25576915
NCI-N87 Growth Inhibition Assay 1 nM-10 μM 72 h IC50 of 5-10 μM, inhibits cell viability dose dependently 25576915
KATOIII Growth Inhibition Assay 1 nM-10 μM 72 h IC50 of 10-100 nM, inhibits cell viability dose dependently 25576915
SNU-16 Growth Inhibition Assay 1 nM-10 μM 72 h IC50 of 10-100 nM, inhibits cell viability dose dependently 25576915
4T1 Growth Inhibition Assay IC50=0.64±0.11 μM 24642893
MDA-MB-468 Growth Inhibition Assay IC50=4.9±0.85 μM 24642893
HCT116 Growth Inhibition Assay IC50=15.9±1.82 μM 24642893
SW620 Growth Inhibition Assay IC50＞20 μM 24642893
MDA-MB-231 Growth Inhibition Assay IC50＞20 μM 24642893
CT26 Growth Inhibition Assay IC50＞20 μM 24642893
SW480 Growth Inhibition Assay IC50＞20 μM 24642893
4T1 Apoptosis Assay 1.25-20 μM 24 h induces apoptosis dose dependently 24642893
KG1a Growth Inhibition Assay IC50=0.018 μM 22369928
Sum52-PE Growth Inhibition Assay IC50=0.041 μM 22369928
KMS11 Growth Inhibition Assay IC50=0.281 μM 22369928
MCF7 Growth Inhibition Assay IC50>30 μM 22369928
KG1 Function assay 72 hrs Inhibition of FGFR1 in human KG1 cells assessed as suppression of cell proliferation after 72 hrs by SRB/CCK-8 assay, IC50 = 0.0002 μM. 27117427
RT112 Function assay 72 hrs Inhibition of FGFR3 in human RT112 cells assessed as suppression of cell proliferation after 72 hrs by SRB/CCK-8 assay, IC50 = 0.0006 μM. 27117427
KG1 Antiproliferative assay 72 hrs Antiproliferative activity against human KG1 cells expressing FGFR1 after 72 hrs, IC50 = 0.0019 μM. 29775937
KG1 Antiproliferative assay 72 hrs Antiproliferative activity against human KG1 cells after 72 hrs by CCK-8 assay, IC50 = 0.0033 μM. 28687204
SNU16 Antiproliferative assay 72 hrs Antiproliferative activity against human SNU16 cells after 72 hrs by CCK-8 assay, IC50 = 0.0034 μM. 28687204
SNU16 Function assay 72 hrs Inhibition of recombinant FGFR2 in human SNU16 cells assessed as suppression of cell proliferation after 72 hrs by SRB/CCK-8 assay, IC50 = 0.0036 μM. 27117427
SNU16 Antiproliferative assay 72 hrs Antiproliferative activity against human SNU16 cells expressing FGFR2 after 72 hrs, IC50 = 0.0062 μM. 29775937
KG1 Antiproliferative assay 72 hrs Antiproliferative activity against FGFR1-translocated human KG1 cells after 72 hrs by CCK8/MTT assay, IC50 = 0.0064 μM. 27348537
SNU16 Antiproliferative assay 72 hrs Antiproliferative activity against FGFR2-amplified human SNU16 cells after 72 hrs by CCK8/MTT assay, IC50 = 0.0134 μM. 27348537
KATO III Function assay 72 hrs Inhibition of FGFR2 in human KATO III cells assessed as inhibition of cell proliferation after 72 hrs by cell counting kit-8 assay, IC50 = 0.0141 μM. 28714692
KG1 Function assay 72 hrs Inhibition of FGFR1OP2 fused FGFR1 in human KG1 cells assessed as inhibition of cell proliferation after 72 hrs by cell counting kit-8 assay, IC50 = 0.0161 μM. 28714692
KATO III Function assay 72 hrs Inhibition of FGFR2 in human KATO III cells assessed as suppression of cell proliferation after 72 hrs by SRB/CCK-8 assay, IC50 = 0.0202 μM. 27117427
SNU16 Function assay 72 hrs Inhibition of FGFR2 in human SNU16 cells assessed as inhibition of cell proliferation after 72 hrs by cell counting kit-8 assay, IC50 = 0.0254 μM. 28714692
UM-UC-14 Antiproliferative assay 72 hrs Antiproliferative activity against human UM-UC-14 cells expressing FGFR3 after 72 hrs, IC50 = 0.0269 μM. 29775937
RT112 Function assay 72 hrs Inhibition of FGFR3 in human RT112 cells assessed as inhibition of cell proliferation after 72 hrs by cell counting kit-8 assay, IC50 = 0.027 μM. 28714692
UM-UC-14 Function assay 72 hrs Inhibition of FGFR3 mutant in human UM-UC-14 cells assessed as inhibition of cell proliferation after 72 hrs by cell counting kit-8 assay, IC50 = 0.0271 μM. 28714692
RT112 Antiproliferative assay 72 hrs Antiproliferative activity against human RT112 cells after 72 hrs by MTT assay, GI50 = 0.0292 μM. 27599742
H1581 Function assay 72 hrs Inhibition of FGFR1 in human H1581 cells assessed as suppression of cell proliferation after 72 hrs by SRB/CCK-8 assay, IC50 = 0.0329 μM. 27117427
NCI-H1581 Antiproliferative assay 72 hrs Antiproliferative activity against human NCI-H1581 cells expressing FGFR1 after 72 hrs, IC50 = 0.04 μM. 29775937
B16F10 Cytotoxicity assay 72 hrs Cytotoxicity against mouse B16F10 cells after 72 hrs by MTT assay, IC50 = 0.051 μM. 25736993
A549 Cytotoxicity assay 72 hrs Cytotoxicity against human A549 cells after 72 hrs by MTT assay, IC50 = 0.062 μM. 25736993
NCI-H1581 Function assay 72 hrs Inhibition of FGFR1 in human NCI-H1581 cells assessed as inhibition of cell proliferation after 72 hrs by cell counting kit-8 assay, IC50 = 0.0626 μM. 28714692
RT112 Antiproliferative assay 72 hrs Antiproliferative activity against human RT112 cells expressing FGFR3 after 72 hrs, IC50 = 0.0838 μM. 29775937
RT112 Antiproliferative assay 72 hrs Antiproliferative activity against FGFR3-amplified human RT112 cells after 72 hrs by CCK8/MTT assay, IC50 = 0.0884 μM. 27348537
NCI-H1581 Antiproliferative assay 72 hrs Antiproliferative activity against FGFR1-amplified human NCI-H1581 cells after 72 hrs by CCK8/MTT assay, IC50 = 0.0921 μM. 27348537
HeLa 229 Cytotoxicity assay 72 hrs Cytotoxicity against human HeLa 229 cells after 72 hrs by MTT assay, IC50 = 0.14 μM. 25736993
BAF3 Antiproliferative assay 72 hrs Antiproliferative activity against mouse BAF3 cells expressing VEGFR2 after 72 hrs, IC50 = 0.222 μM. 29775937
SGC7901 Antiproliferative assay 72 hrs Antiproliferative activity against human SGC7901 cells after 72 hrs by MTT assay, IC50 = 2.8 μM. 27829519
MGC803 Antiproliferative assay 72 hrs Antiproliferative activity against human MGC803 cells after 72 hrs by MTT assay, IC50 = 6.2 μM. 27829519
BGC823 Antiproliferative assay 72 hrs Antiproliferative activity against human BGC823 cells after 72 hrs by MTT assay, IC50 = 7.9 μM. 27829519
HL7702 Cytotoxicity assay 72 hrs Cytotoxicity against human HL7702 cells after 72 hrs by MTT assay, IC50 = 18.21 μM. 25736993
U-2 OS qHTS ssay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for U-2 OS cells 29435139
A673 qHTS ssay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for A673 cells 29435139
Saos-2 qHTS ssay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Saos-2 cells 29435139
BT-37 qHTS ssay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-37 cells 29435139
RD qHTS ssay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for RD cells 29435139
SK-N-SH qHTS ssay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-SH cells 29435139
BT-12 qHTS ssay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-12 cells 29435139
OHS-50 qHTS ssay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for OHS-50 cells 29435139
fibroblast cells qHTS ssay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for control Hh wild type fibroblast cells 29435139
Rh41 qHTS ssay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh41 cells 29435139
Rh30 qHTS ssay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh30 cells 29435139
SJ-GBM2 qHTS ssay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SJ-GBM2 cells 29435139
NB-EBc1 qHTS ssay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB-EBc1 cells 29435139
LAN-5 qHTS ssay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for LAN-5 cells 29435139
Rh18 qHTS ssay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh18 cells 29435139
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화학 정보, 보관 및 안정성 (Chemical Information, Storage & Stability)

분자량 463.57 화학식

C26H33N5O3

 보관 (수령일로부터)
CAS 번호 1035270-39-3 SDF 다운로드 원액 보관

동의어 ABSK 091 Smiles CC1CN(CC(N1)C)C2=CC=C(C=C2)C(=O)NC3=NNC(=C3)CCC4=CC(=CC(=C4)OC)OC

용해도 (Solubility)

In vitro
배치:

DMSO : 93 mg/mL (200.61 mM)
(수분으로 오염된 DMSO는 용해도를 감소시킬 수 있습니다. 신선하고 무수 DMSO를 사용하십시오.)

Ethanol : 40 mg/mL

Water : 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)

특징
Greater selectivity for FGFR1-3 over FGFR4. AZD4547 is active against the tyrosine kinase activity of both the wild-type and mutant forms of FGFR.
Targets/IC50/Ki
FGFR1
(Cell-free assay)
0.2 nM
FGFR3
(Cell-free assay)
1.8 nM
FGFR2
(Cell-free assay)
2.5 nM
KDR
(Cell-free assay)
24 nM
시험관 내(In vitro)

Compared to FGFR1-3, AZD4547 displays weaker activity against FGFR4 with IC50 of 165 nM. AZD4547 only inhibits recombinant VEGFR2 (KDR) kinase activity with IC50 of 24 nM, in the in vitro selectivity test against a diverse panel of representative human kinases. AZD4547 at 0.1 μM exhibits no activity against a range of recombinant kinases including ALK, CHK1, EGFR, MAPK1, MEK1, p70S6K, PDGFR, PKB, Src, Tie2, and PI3-kinase. Consistently, the potent selectivity of AZD4547 for FGFR1-3 over FGFR4, IGFR, and KDR is also observed in cellular phosphorylation assays. AZD4547 has potent in vitro antiproliferative activity only against tumor cell lines expressing deregulated FGFRs such as KG1a, Sum52-PE, and KMS11 with IC50 of 18-281 nM, and is inactive against MCF7 as well as more than 100 additional tumor cell lines. AZD4547 treatment potently inhibits FGFR and MAPK phosphorylation in human tumor cell lines in a dose-dependent manner. AZD4547 also potently inhibits the phosphorylation of FRS2 and PLCγ, downstream markers of FGFR signaling. Notably, AZD4547 affects the AKT phosphorylation in the breast cell lines, MCF7 and Sum52-PE but not in KG1a and KMS11 lines. AZD4547 treatment significantly induces apoptosis in Sum52-PE and KMS11 cells, dramatically increases G1 arrest but not apoptosis in KG1a cells, and has no effect on cell cycle distribution or apoptosis in MCF7 cells.

키나아제 분석
AZD4547 (Fexagratinib) 키나아제 활성
AZD4547 (Fexagratinib)이 FGFR1-3의 인간 재조합 키나아제 활성을 억제하는 능력은 각각의 Km 값과 같거나 그보다 약간 낮은 ATP 농도를 사용하여 테스트되었습니다.
생체 내(In vivo)

Oral administration of AZD4547 at 3 mg/kg twice daily in mice bearing KMS11 tumors results in significant tumor growth inhibition of 53% when compared with vehicle-treated controls, and AZD4547 at 12.5 mg/kg once daily or 6.25 mg/kg twice daily leads to complete tumor stasis, which is associated with dose proportional pharmacodynamic modulation of phospho-FGFR3 and reduced KMS11 tumor cell proliferation. Moreover, oral administration of AZD4547 at 12.5 mg/kg once daily results in 65% tumor growth inhibition in the FGFR1-fusion KG1a xenograft model. At efficacious dose levels, AZD4547 does not exhibit antiangiogenic effects. AZD4547 has no significant effect on blood pressure and therefore lacks in vivo anti-KDR activity. Consistently, dosing of 6.25 mg/kg orally twice daily AZD4547 is inactive in the cediranib-sensitive xenograft models including Calu-6, HCT-15 and LoVo.

참조

적용 분야 (Applications)

방법 바이오마커 이미지 PMID
Western blot p-FGFR / FGFR1 / p-AKT / AKT / p-ERK / ERK pFRS2
S2801-WB1
28900173
Growth inhibition assay Cell viability Cell viability
S2801-viability1
28900173

임상시험 정보 (Clinical Trial Information)

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

NCT 번호 모집 조건 스폰서/협력자 시작일 단계
NCT02824133 Completed
Recurrent IDHwt Gliomas With FGFR3-TACC3 Fusion|Recurrent IDHwt Gliomas With FGFR1-TACC1 Fusion
Assistance Publique - Hôpitaux de Paris
 September 2015 Phase 1|Phase 2
NCT01824901 Completed
Recurrent Non-small Cell Lung Cancer|Squamous Cell Lung Cancer
ECOG-ACRIN Cancer Research Group|National Cancer Institute (NCI)|Eastern Cooperative Oncology Group
 January 15 2014 Phase 1|Phase 2
NCT01795768 Unknown status
Gastric Cancer|Oesophageal Cancer|Breast Cancer|Squamous Cell Carcinoma of the Lung
Royal Marsden NHS Foundation Trust|AstraZeneca
 September 2012 Phase 2
NCT01213160 Completed
Cancer|Advanced Solid Malignancies
AstraZeneca
 November 2010 Phase 1