Home Protein Tyrosine Kinase c-Met inhibitor Tivantinib

연구용

Tivantinib c-Met inhibitor

제품 번호: S2753

Tivantinib is the first non-ATP-competitive c-Met inhibitor with Ki of 0.355 μM in a cell-free assay, little activity to Ron, and no inhibition to EGFR, InsR, PDGFRα or FGFR1/4. This compound induces a G2/M arrest and apoptosis.
Tivantinib c-Met inhibitor Chemical Structure

화학 구조

분자량: 369.42

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품질 관리 (Quality Control)

배치: 순도: 99.65%
99.65

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

세포주 분석 유형 농도 배양 시간 제형 활성 설명 PMID
MNK-45 Kinase assay ~10 μM inhibits c-Met phosphorylation and downstream c-Met signaling pathways
HT29 Kinase assay ~10 μM inhibits c-Met phosphorylation and downstream c-Met signaling pathways
MDA-MB-231 Kinase assay ~10 μM inhibits c-Met phosphorylation and downstream c-Met signaling pathways
NCI-H441 Kinase assay ~10 μM inhibits c-Met phosphorylation and downstream c-Met signaling pathways
SK-MEL-28 Growth inhibitory assay 33 μM IC50>33 μM
NCI-H661 Growth inhibitory assay 33 μM IC50>33 μM
NCI-H446 Growth inhibitory assay 33 μM IC50=7 μM
MDA-MB-231 Growth inhibitory assay 33 μM IC50=0.55 μM
DLD-1 Growth inhibitory assay 33 μM IC50=0.53 μM
A549 Growth inhibitory assay 33 μM IC50=0.59 μM
SK-OV-3 Growth inhibitory assay 33 μM IC50=0.66 μM
NCI-H460 Growth inhibitory assay 33 μM IC50=0.6 μM
A375 Growth inhibitory assay 33 μM IC50=0.42 μM
NCI-H441 Growth inhibitory assay 33 μM IC50=0.3 μM
HT29 Growth inhibitory assay 33 μM IC50=0.49 μM
MKN-45 Growth inhibitory assay 33 μM IC50=0.58 μM
HT29 Apoptosis assay ~10 μM significantly induces apoptosis by 80-90%.
MKN-45 Apoptosis assay ~10 μM significantly induces apoptosis by 80-90%.
MDA-MB-231 Apoptosis assay ~10 μM modestly induces apoptosis by 35%.
MDA-MB-231/TGL Growth inhibitory assay ~100 μM GI50=1.2 μM
1833/TGL Growth inhibitory assay ~100 μM GI50=3.7 μM
EBC1 Cytotoxic assay ~10 μM inhibits the cell growth.
SNU638 Cytotoxic assay ~10 μM inhibits the cell growth.
A549 Cytotoxic assay ~10 μM not affect
H460 Cytotoxic assay ~10 μM not affect
HCC827 Cytotoxic assay ~10 μM not affect
A549 Function assay 10 μM disrupts microtubule
EBC1 Function assay 10 μM disrupts microtubule
H460 Function assay 10 μM inhibits tubulin polymerization
K562/VCR Cytotoxic assay ~10 μM shows cytotoxic activity
CEM/VBL Cytotoxic assay ~10 μM shows cytotoxic activity
U266 Cytotoxic assay ~3 μM  IC50=1.1 μM
OPM-2 Cytotoxic assay ~3 μM  IC50=1.8 μM
MM.1S Cytotoxic assay ~3 μM  IC50=1.6 μM
MM.1R Growth inhibitory assay 3 μM  inhibits cell growth by 49%
RPMI-8226 Cytotoxic assay ~3 μM  IC50=0.9 μM
ANBL-6 Cytotoxic assay 1 μM  induces cell death by more than 50%
ANLB-6/V10R Cytotoxic assay 1 μM  induces cell death by more than 50%
KAS-6/1 Cytotoxic assay 1 μM  induces cell death by more than 50%
KAS-6/V10R Cytotoxic assay 1 μM  induces cell death by more than 50%
KAS-6/R10R Cytotoxic assay 1 μM  induces cell death by more than 50%
8226/S Growth inhibitory assay 3 μM  inhibits cell growth by 54%
8226/LR-5 Growth inhibitory assay 3 μM  inhibits cell growth by 54%
Huh7 Cytotoxic assay ~4.8 μM  DMSO IC50=9.9 nM
Hep3B Cytotoxic assay ~4.8 μM  DMSO IC50=448.7 nM
HepG2 Cytotoxic assay ~4.8 μM  DMSO IC50=139.77 nM
Chang Cytotoxic assay ~4.8 μM  DMSO IC50=448.7 nM
Huh7 Function assay 1.6 μM  DMSO causes a G2/M cell cycle arrest
Hep3B Function assay 1.6 μM  DMSO causes a G2/M cell cycle arrest
HepG2 Function assay 1.6 μM  DMSO causes a G2/M cell cycle arrest
Chang Function assay 1.6 μM  DMSO causes a G2/M cell cycle arrest
MHCC97L Growth inhibitory assay ~10 μM DMSO IC50=315 nM
MHCC97H Growth inhibitory assay ~10 μM DMSO IC50=368  nM
Huh7 Growth inhibitory assay ~10 μM DMSO IC50=265 nM
HepG2 Growth inhibitory assay ~10 μM DMSO IC50=392 nM
MHCC97L Function assay 1 μM  DMSO induces microtubules depolymerization
Huh7 Function assay 1 μM  DMSO induces microtubules depolymerization
MHCC97L Apoptosis assay 1 μM  DMSO induces apoptosis
Huh7 Apoptosis assay 1 μM  DMSO induces apoptosis
C3H 10T1/2 mouse fibroblasts Kinase assay 25 μM DMSO reduces Histone H3 and H4 acetylation levels 
H23 Growth inhibitory assay 25 μM DMSO significantly inhibits cell growth.
WM35 Growth inhibitory assay 10 μM DMSO significantly inhibits cell growth.
NIH 3T3 Growth inhibitory assay 10 μM DMSO does not have a significant inhibitory effect
H838 Growth inhibitory assay 10 μM DMSO does not have a significant inhibitory effect
H1395 Growth inhibitory assay 10 μM DMSO does not have a significant inhibitory effect
Quiescent S2 Kinase assay 30 μM DMSO completely abrogates TSA-induced hyperacetylation of H3K4me3 histones
PC3 Apoptosis assay 20 μM DMSO induces apoptosis
Du145 Apoptosis assay 20 μM DMSO induces apoptosis
LNCaP Apoptosis assay 20 μM DMSO induces apoptosis
LAPC-4 Apoptosis assay 20 μM DMSO induces apoptosis
LNCaP Function assay 20 μM DMSO decreases PSA secretion and p65 expression levels
LAPC-4 Function assay 20 μM DMSO decreases PSA secretion and p65 expression levels
Kasumi-1 Growth inhibitory assay ~50 μM DMSO inhibits cell proliferation
SKNO-1 Growth inhibitory assay ~50 μM DMSO inhibits cell proliferation
Kasumi-1 Kinase assay ~10 μM DMSO reduces expression of acetylated histone H3, c-kit and bcl-2
SKNO-1 Kinase assay ~10 μM DMSO reduces expression of acetylated histone H3, c-kit and bcl-2
A549 Function assay 10 μM DMSO enhances mitotic catastrophe
NRK-52E Function assay 10 μM DMSO inhibits Ang II-induced STAT3 nuclear translocation and the expression of TGF-β1, collagen IV and fibronectin
PC12 Growth inhibitory assay ~12.5 μM DMSO prevents TSA-induced neurite formation
HPMCs Function assay reverses epithelial to mesenchymal transition of human peritoneal mesothelial cells
A549 Function assay ~50 μM DMSO affects the viral life cycle and host response
RAW264.7 Function assay ~30 μM DMSO reduces pro-inflammatory gene expression
MEMM Kinase assay 15 µM DMSO decreases acetylation of histone H3
MEMM Growth inhibitory assay ~20 µM DMSO inhibits cell proliferation
MEMM Apoptosis assay 15 µM DMSO induces the presence of the apoptosis protein, cleaved Caspase-3
T47D Growth inhibitory assay 10 μM DMSO IC50=72 nM
ZR-75-1 Growth inhibitory assay 10 μM DMSO IC50=79 nM
BT474 Growth inhibitory assay 10 μM DMSO IC50=86 nM
HCC1954 Growth inhibitory assay 10 μM DMSO IC50=119 nM
MDA-MB-453 Growth inhibitory assay 10 μM DMSO IC50=975 nM
MDA-MB-468 Growth inhibitory assay 10 μM DMSO IC50=3208 nM
SkBr3 Growth inhibitory assay 10 μM DMSO IC50>10,000 nM
MDA-MB-231 Growth inhibitory assay 10 μM DMSO IC50>10,000 nM
HCT116 Growth inhibitory assay 10 μM DMSO IC50=5836 nM
HT29 Growth inhibitory assay 10 μM DMSO IC50>10,000 nM
HFF Growth inhibitory assay 10 μM DMSO IC50=7615 nM
HN5 Growth inhibitory assay 10 μM DMSO IC50>10,000 nM
786-0 Growth inhibitory assay 10 μM DMSO IC50=4009 nM
H157 Growth inhibitory assay 10 μM DMSO IC50=2642 nM
NCI-H460 Growth inhibitory assay 10 μM DMSO IC50>2,500 nM
SKOV-3 Growth inhibitory assay 10 μM DMSO IC50=2126 nM
OVCAR-3 Growth inhibitory assay 10 μM DMSO IC50=2918 nM
BXPC3 Growth inhibitory assay 10 μM DMSO IC50=3141 nM
MiaPaCa Growth inhibitory assay 10 μM DMSO IC50=5433 nM
PANC-1 Growth inhibitory assay 10 μM DMSO IC50=8681 nM
LNCaP Growth inhibitory assay 10 μM DMSO IC50=147 nM
DU145 Growth inhibitory assay 10 μM DMSO IC50=3812 nM
PC3 Growth inhibitory assay 10 μM DMSO IC50>10,000 nM
BT474 Kinase assay 10 μM DMSO inhibits pGSK3β with IC50 of 160 nM
786-0 Kinase assay 10 μM DMSO inhibits pGSK3β with IC50 of 150 nM
LNCaP Kinase assay 10 μM DMSO inhibits pGSK3β with IC50 of 43 nM
PC3 Kinase assay 10 μM DMSO inhibits pGSK3β with IC50 of 49 nM
KARPAS-231 Growth inhibitory assay 10 μM DMSO EC50=41 nM
CCRFSB Growth inhibitory assay 10 μM DMSO EC50=155 nM
SUP B15 Growth inhibitory assay 10 μM DMSO EC50=197 nM
SD-1 Growth inhibitory assay 10 μM DMSO EC50=320 nM
RS4;11 Growth inhibitory assay 10 μM DMSO EC50=654 nM
MN-60 Growth inhibitory assay 10 μM DMSO EC50=3602 nM
Tanoue Growth inhibitory assay 10 μM DMSO EC50=4517 nM
RCH-ACV Growth inhibitory assay 10 μM DMSO EC50=152 nM
SEM Growth inhibitory assay 10 μM DMSO EC50=202 nM
KASUMI-2 Growth inhibitory assay 10 μM DMSO EC50=225 nM
REH Growth inhibitory assay 10 μM DMSO EC50=288 nM
697 Growth inhibitory assay 10 μM DMSO EC50=338 nM
NALM-6 Growth inhibitory assay 10 μM DMSO EC50=421 nM
MHH-CALL–3 Growth inhibitory assay 10 μM DMSO EC50=812 nM
MHH-CALL–2 Growth inhibitory assay 10 μM DMSO EC50=2114 nM
J.GAMMA-1 Growth inhibitory assay 10 μM DMSO EC50=65 nM
JR45.01 Growth inhibitory assay 10 μM DMSO EC50=68 nM
A3 Growth inhibitory assay 10 μM DMSO EC50=69 nM
I 2.1 Growth inhibitory assay 10 μM DMSO EC50=73 nM
MOLT-3 Growth inhibitory assay 10 μM DMSO EC50=74 nM
P116 Growth inhibitory assay 10 μM DMSO EC50=78 nM
J.Cam1.6 Growth inhibitory assay 10 μM DMSO EC50=79 nM
I 9.2 Growth inhibitory assay 10 μM DMSO EC50=80 nM
LOUCY Growth inhibitory assay 10 μM DMSO EC50=117 nM
J.RT3-T3.5 Growth inhibitory assay 10 μM DMSO EC50=123 nM
800000 Growth inhibitory assay 10 μM DMSO EC50=163 nM
Jurkat Growth inhibitory assay 10 μM DMSO EC50=225 nM
MOLT-4 Growth inhibitory assay 10 μM DMSO EC50=232 nM
Molt-16 Growth inhibitory assay 10 μM DMSO EC50=241 nM
CEM/C3 Growth inhibitory assay 10 μM DMSO EC50=257 nM
CEM/C2 Growth inhibitory assay 10 μM DMSO EC50=271 nM
CCRFCEM Growth inhibitory assay 10 μM DMSO EC50=327 nM
CEM/C1 Growth inhibitory assay 10 μM DMSO EC50=382 nM
SUPTI[VB] Growth inhibitory assay 10 μM DMSO EC50=619 nM
CCRF–HSB-2 Growth inhibitory assay 10 μM DMSO EC50=2117 nM
I 2.1 Apoptosis assay 10 μM DMSO induces apoptosis
I 9.2 Apoptosis assay 10 μM DMSO induces apoptosis
A3 Apoptosis assay 10 μM DMSO induces apoptosis
RD Growth inhibitory assay 10 μM IC50>10 μM
Rh41 Growth inhibitory assay 10 μM IC50=33.8 nM
Rh18 Growth inhibitory assay 10 μM IC50=303 nM
Rh30 Growth inhibitory assay 10 μM IC50=4.81 μM
BT-12 Growth inhibitory assay 10 μM IC50>10 μM
CHLA-266 Growth inhibitory assay 10 μM IC50=1.22 μM
TC-71 Growth inhibitory assay 10 μM IC50=2.52 μM
CHLA-9 Growth inhibitory assay 10 μM IC50=591 nM
CHLA-10 Growth inhibitory assay 10 μM IC50=102 nM
CHLA-258 Growth inhibitory assay 10 μM IC50=1.05 μM
GBM2 Growth inhibitory assay 10 μM IC50=9.15 μM
NB-1643 Growth inhibitory assay 10 μM IC50=5.4 μM
NB-Ebc1 Growth inhibitory assay 10 μM IC50>10 μM
CHLA-90 Growth inhibitory assay 10 μM IC50>10 μM
CHLA-136 Growth inhibitory assay 10 μM IC50>10 μM
NALM-6 Growth inhibitory assay 10 μM IC50=265 nM
COG-LL-317 Growth inhibitory assay 10 μM IC50=6.49 nM
RS4;11 Growth inhibitory assay 10 μM IC50=147 nM
MOLT-4 Growth inhibitory assay 10 μM IC50=40 nM
CCRF-CEM Growth inhibitory assay 10 μM IC50=268 nM
Kasumi-1 Growth inhibitory assay 10 μM IC50=107 nM
Karpas-299 Growth inhibitory assay 10 μM IC50=2.93 μM
Ramos-RA1 Growth inhibitory assay 10 μM IC50=7.35 μM
H1299 Kinase assay 10 μM inhibits IKBKE-induced Akt Activation
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화학 정보, 보관 및 안정성 (Chemical Information, Storage & Stability)

분자량 369.42 화학식

C23H19N3O2

 보관 (수령일로부터)
CAS 번호 905854-02-6 SDF 다운로드 원액 보관

동의어 ARQ 197 Smiles C1CC2=C3C(=CC=C2)C(=CN3C1)C4C(C(=O)NC4=O)C5=CNC6=CC=CC=C65

용해도 (Solubility)

In vitro
배치:

DMSO : 73 mg/mL (197.6 mM)
(수분으로 오염된 DMSO는 용해도를 감소시킬 수 있습니다. 신선하고 무수 DMSO를 사용하십시오.)

Ethanol : 35 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
The first selective c-Met inhibitor to be advanced into human clinical trials.
Targets/IC50/Ki
c-Met
(Cell-free assay)
0.355 μM(Ki)
시험관 내(In vitro)

ARQ-197 has been shown to prevent HGF/c-met induced cellular responses in vitro. This compound possesses antitumor activity; inhibiting proliferation of A549, DBTRG and NCI-H441 cells with IC50 of 0.38, 0.45, 0.29 μM. Treatment with this agent results in a decrease in phosphorylation of the MAPK signaling cascade and prevention of invasion and migration. In addition, ectopic expression of c-Met in NCI-H661, a cell line having no endogenous expression of c-Met, causes it to acquire an invasive phenotype that is also suppressed by this chemical. Although the addition of increasing concentrations of this inhibitor does not significantly affect the Km of ATP, exposure of c-Met to 0.5 μM of this substance decreased the Vmax of c-Met by approximately 3-fold. The ability of this molecule to decrease the Vmax without affecting the Km of ATP confirmed that it inhibits c-Met through a non–ATP-competitive mechanism and may therefore account for its high degree of kinase selectivity. It prevents human recombinant c-Met with a calculated inhibitory constant Ki of approximately 355 nM. Although the highest concentration of ATP used is 200 μM, the potency of this compound against c-Met is not reduced by using concentrations of ATP up to 1 mM. It blocks c-Met phosphorylation and downstream c-Met signaling pathways. This chemical suppresses constitutive and ligand-mediated c-Met autophosphorylation and, by extension, c-Met activity, in turn leading to the inhibition of downstream c-Met effectors. Its induction of caspase-dependent apoptosis is increased in c-Met–expressing human cancer cells including HT29, MKN-45, and MDA-MB-231 cells.
키나아제 분석
c-Met SDS-PAGE in vitro kinase assay
재조합 c-Met 단백질(100 ng)을 상온에서 30분 동안 이 화합물의 농도를 증가시키며 전배양합니다. 전배양 후, 100 μM의 poly-Glu-Tyr 기질과 5 μCi의 [γ-32P]ATP를 포함하는 다양한 농도의 ATP를 반응 혼합물에 첨가합니다. 반응액을 상온에서 5분간 배양한 후, 5 μL의 SDS-폴리아크릴아미드 젤 및 환원 샘플 버퍼를 첨가하여 반응을 정지시킵니다. 그 다음 샘플을 7.5% 아크릴아미드 젤에 로딩하고 SDS-PAGE를 수행합니다. 인산화된 poly-Glu-Tyr 기질은 최종적으로 자기방사법(autoradiography)을 통해 시각화합니다. c-Met 활성은 농도계측법(densitometry)으로 정량화합니다.
생체 내(In vivo)

All three xenograft models treated with Tivantinib display reductions in tumor growth: 66% in the HT29 model, 45% in the MKN-45 model, and 79% in the MDA-MB-231 model. In these xenograft studies, no significant body weight changes following oral administration of this compound at 200 mg/kg are observed. Pharmacodynamically, the phosphorylation of c-Met in human colon xenograft tumors (HT29) is strongly inhibited by this chemical, as assessed by a dramatic reduction of c-Met autophosphorylation 24 hours after a single oral dose of 200 mg/kg of this agent. This same dosage in mice exhibits that tumor xenografts are exposed to sustained plasma levels of the compound, consistent with the observed pharmacodynamic inhibition of c-Met phosphorylation and inhibition of proliferation of c-Met harboring cancer cell lines. Plasma levels of the agent 10 hours after dosing are determined to be 1.3 μM, more than 3-fold above the biochemical inhibitory constant of this substance for c-Met. Therefore, it is able to suppress its target in vivo in the xenografted human tumor tissue. In conclusion, this inhibitor blocks the growth of c-Met-dependent xenografted human tumors.
참조

적용 분야 (Applications)

방법 바이오마커 이미지 PMID
Western blot cMET / p-cMET / p-AKT / p-ERK / p-rpS6
S2753-WB1
23022995
Growth inhibition assay Cell viability
S2753-viability1
23598276

임상시험 정보 (Clinical Trial Information)

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

NCT 번호 모집 조건 스폰서/협력자 시작일 단계
NCT02150733 Completed
Hepatic Impairment|Solid Tumor|Cancer
Daiichi Sankyo|Medpace Inc.
 April 2014 Phase 1
NCT01892527 Completed
Colorectal Cancer Metastatic|C-met Overexpression
Armando Santoro MD|Istituto Clinico Humanitas
 March 2013 Phase 2
NCT02049060 Completed
Malignant Pleural Mesothelioma|Nonsquamous Nonsmall Cell Neoplasm of Lung
Armando Santoro MD|Istituto Clinico Humanitas
 January 2013 Phase 1|Phase 2
NCT01755767 Completed
Hepatocellular Carcinoma
Daiichi Sankyo|ArQule Inc. a subsidiary of Merck Sharp & Dohme LLC a subsidiary of Merck & Co. Inc. (Rahway NJ USA)
 December 27 2012 Phase 3

자주 묻는 질문 (Frequently Asked Questions)

질문 1:
Are there any other solutions (apart from DMSO) I can dissolve it for in vivo experiment?

답변:
S2753 This compound (ARQ 197) can be dissolved in 1% methylcellulose at 15 mg/ml as a suspension.