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Foretinib (GSK1363089, XL880) Multi-targeted Tyrosine Kinase Inhibitor

Name: Foretinib (GSK1363089, XL880)
Brand: Selleck Chemicals
SKU: S1111
Rating: 5 (94 reviews)

Réf. Catalogue: S1111

Foretinib is an ATP-competitive inhibitor of HGFR and VEGFR, mostly for Met (c-Met) and KDR with IC50 of 0.4 nM and 0.9 nM in cell-free assays. Less potent against Ron, Flt-1/3/4, Kit (c-Kit), PDGFRα/β and Tie-2, and little activity to FGFR1 and EGFR. Phase 2.

Foretinib (GSK1363089, XL880) c-Met inhibitor Chemical Structure

Structure chimique

Poids moléculaire: 632.65

Aller à

Contrôle Qualité (Quality Control)

Lot : Pureté : 99.94%

99.94

Cibles apparentées	EGFR VEGFR FGFR PDGFR Src MEK CSF-1R FLT3 HER2 c-Kit
Autre c-Met Inhibiteurs	Tepotinib (EMD-1214063) Dihexa SGX-523 PHA-665752 SU11274 BMS-777607 JNJ-38877605 Tivantinib PF-04217903 Savolitinib (AZD6094)

Culture cellulaire, traitement et concentration de travail
(Cell Culture, Treatment & Working Concentration)

Lignées cellulaires	Type d'essai	Concentration	Temps d'incubation	Formulation	Description de l'activité	PMID
Daoy	Function Assay	0.5/1/2.5 μM	24 h	DMSO	inhibits the HGF-induced cMET pathway activation	25391241
ONS76	Function Assay	0.5/1/2.5 μM	24 h	DMSO	inhibits the HGF-induced cMET pathway activation	25391241
Daoy	Function Assay	0.5/1/2.5 μM	24 h	DMSO	inhibits HGF-mediated migration and invasion	25391241
ONS76	Function Assay	0.5/1/2.5 μM	24 h	DMSO	inhibits HGF-mediated migration and invasion	25391241
Daoy	Apoptosis Assay	1 μM	24 h	DMSO	induces apoptosis	25391241
Daoy	Growth Inhibition Assay	0.5/1/2.5 μM	24-96 h	DMSO	inhibits cell growth in a dose dependent manner	25391241
U251	Function Assay	100/300/900 nM	1 h	DMSO	inhibits the phosphorylation of MerTK	24658326
A172	Function Assay	100/300/900 nM	1 h	DMSO	inhibits the phosphorylation of MerTK	24658326
SF188	Function Assay	100/300/900 nM	1 h	DMSO	inhibits the phosphorylation of MerTK	24658326
U251	Function Assay	100/300/900 nM	1 h	DMSO	inhibits the activity of Axl, Tyro3	24658326
A172	Function Assay	100/300/900 nM	1 h	DMSO	inhibits the activity of Axl, Tyro3	24658326
SF188	Function Assay	100/300/900 nM	1 h	DMSO	inhibits the activity of Axl, Tyro3	24658326
U251	Function Assay	100/300/900 nM	1 h	DMSO	decreases Akt phosphorylation in a concentration dependent manner	24658326
A172	Function Assay	100/300/900 nM	1 h	DMSO	decreases Akt phosphorylation in a concentration dependent manner	24658326
SF188	Function Assay	100/300/900 nM	1 h	DMSO	decreases Akt phosphorylation in a concentration dependent manner	24658326
U251	Function Assay	100/300/900 nM	28 h	DMSO	induces PARP cleavage	24658326
SF188	Function Assay	100/300/900 nM	28 h	DMSO	induces PARP cleavage	24658326
SF188	Growth Inhibition Assay	100/300/900 nM	48 h	DMSO	reduces cell survival at 900 nM significantly	24658326
U251	Growth Inhibition Assay	100/300/900 nM	48 h	DMSO	reduces cell survival at 900 nM significantly	24658326
A172	Growth Inhibition Assay	100/300/900 nM	48 h	DMSO	reduces cell survival at 900 nM significantly	24658326
SF188	Function Assay	100/300/900 nM	24 h	DMSO	abrogates migration and invasion of glioma cells in a dose dependent manner	24658326
U251	Function Assay	100/300/900 nM	24 h	DMSO	abrogates migration and invasion of glioma cells in a dose dependent manner	24658326
A172	Function Assay	100/300/900 nM	24 h	DMSO	abrogates migration and invasion of glioma cells in a dose dependent manner	24658326
Ba/F3	Cell Viability Assay	0.0001-10 μM	72 h		inhibits cell growth in a dose dependent manner	24218589
HCC78	Cell Viability Assay	0.01-10 μM	72 h		inhibits cell growth in a dose dependent manner	24218589
SK-HEP1	Cell Viability Assay	0.25-1.5 μM	24 h		inhibits cell growth in a dose dependent manner	22187171
SK-HEP2	Function Assay	1 μM	24 h		blocks HGF-induced cell motility	22187171
SK-HEP2	Function Assay	1 μM	24 h		causes G2/M phase arrest with reduction in the G0/G1 and S phases	22187171
MKN-45	Growth Inhibition Assay	0.01-10 μM	5 d		IC50=8 nM	21655918
KATO-III	Growth Inhibition Assay	0.01-10 μM	5 d		IC50=30 nM	21655918
MKN-45	Function Assay	1 μM	24 h		inhibits phosphorylation of MET, Akt, and ERK1/2 in MKN-45	21655918
KATO-III	Function Assay	1 μM	24 h		inhibits phosphorylation of MET, Akt, and ERK1/2 in MKN-45	21655918
H1648	Growth Inhibition Assay				IC50=1.28 ±0.12 μM	21252284
H1573	Growth Inhibition Assay				IC50=1.62 ± 0.05 μM	21252284
H596	Growth Inhibition Assay				IC50=1.21 ± 0.17 μM	21252284
HOP92	Growth Inhibition Assay				IC50=0.81 ± 0.29 μM	21252284
H69	Growth Inhibition Assay				IC50=1.18 ± 0.08 μM	21252284
H1975	Growth Inhibition Assay				IC50=1.39 ± 0.33 μM	21252284
SCC15	Growth Inhibition Assay				IC50=0.63 ± 0.04 μM	21252284
HN5	Growth Inhibition Assay				IC50=0.65 ± 0.26 μM	21252284
MKN45	Cytotoxicity assay		72 hrs		Cytotoxicity against c-Met-dependent human MKN45 cells assessed as growth inhibition after 72 hrs by MTT assay, IC50 = 0.03 μM.	23628470
A549	Cytotoxicity assay		72 hrs		Cytotoxicity against c-Met-dependent human A549 cells assessed as growth inhibition after 72 hrs by MTT assay, IC50 = 0.08 μM.	23628470
HT-29	Cytotoxicity assay		72 hrs		Cytotoxicity against c-Met-dependent human HT-29 cells assessed as growth inhibition after 72 hrs by MTT assay, IC50 = 0.15 μM.	23628470
H460	Cytotoxicity assay		72 hrs		Cytotoxicity against c-Met-independent human H460 cells assessed as growth inhibition after 72 hrs by MTT assay, IC50 = 0.18 μM.	23628470
SMMC7721	Cytotoxicity assay		72 hrs		Cytotoxicity against c-Met-dependent human SMMC7721 cells assessed as growth inhibition after 72 hrs by MTT assay, IC50 = 0.44 μM.	23628470
U87MG	Cytotoxicity assay		72 hrs		Cytotoxicity against c-Met-dependent human U87MG cells assessed as growth inhibition after 72 hrs by MTT assay, IC50 = 0.9 μM.	23628470
MKN45	Cytotoxicity assay		72 hrs		Cytotoxicity against human MKN45 cells after 72 hrs by MTT assay, IC50 = 0.031 μM.	23644189
H460	Cytotoxicity assay		72 hrs		Cytotoxicity against human H460 cells after 72 hrs by MTT assay, IC50 = 0.12 μM.	23644189
HT-29	Cytotoxicity assay		72 hrs		Cytotoxicity against human HT-29 cells after 72 hrs by MTT assay, IC50 = 0.18 μM.	23644189
SMMC7721	Cytotoxicity assay		72 hrs		Cytotoxicity against human SMMC7721 cells after 72 hrs by MTT assay, IC50 = 0.3 μM.	23644189
U87MG	Cytotoxicity assay		72 hrs		Cytotoxicity against human U87MG cells after 72 hrs by MTT assay, IC50 = 1.04 μM.	23644189
MKN45	Cytotoxicity assay				Cytotoxicity against human MKN45 cells, IC50 = 0.008 μM.	23838381
MKN45	Cytotoxicity assay		72 hrs		Cytotoxicity against human MKN45 cells after 72 hrs by MTT assay, IC50 = 0.023 μM.	23838381
A549	Cytotoxicity assay		72 hrs		Cytotoxicity against human A549 cells after 72 hrs by DAPI staining-based fluorescence assay, IC50 = 0.029 μM.	23838381
HT-29	Cytotoxicity assay		72 hrs		Cytotoxicity against human HT-29 cells after 72 hrs by DAPI staining-based fluorescence assay, IC50 = 0.165 μM.	23838381
A549	Cytotoxicity assay		72 hrs		Cytotoxicity against human A549 cells after 72 hrs by MTT assay, IC50 = 0.17 μM.	23838381
NCI-H460	Cytotoxicity assay		72 hrs		Cytotoxicity against human NCI-H460 cells after 72 hrs by MTT assay, IC50 = 0.21 μM.	23838381
HT-29	Cytotoxicity assay		72 hrs		Cytotoxicity against human HT-29 cells after 72 hrs by MTT assay, IC50 = 0.26 μM.	23838381
SMMC7721	Cytotoxicity assay		72 hrs		Cytotoxicity against human SMMC7721 cells after 72 hrs by MTT assay, IC50 = 0.32 μM.	23838381
U87MG	Cytotoxicity assay		72 hrs		Cytotoxicity against human U87MG cells after 72 hrs by MTT assay, IC50 = 0.47 μM.	23838381
MKN45	Cytotoxicity assay		72 hrs		Cytotoxicity against human MKN45 cells after 72 hrs by MTT assay, IC50 = 0.032 μM.	24012712
A549	Cytotoxicity assay		72 hrs		Cytotoxicity against human A549 cells after 72 hrs by MTT assay, IC50 = 0.11 μM.	24012712
HT-29	Cytotoxicity assay		72 hrs		Cytotoxicity against human HT-29 cells after 72 hrs by MTT assay, IC50 = 0.19 μM.	24012712
H460	Cytotoxicity assay		72 hrs		Cytotoxicity against human H460 cells after 72 hrs by MTT assay, IC50 = 0.21 μM.	24012712
U87MG	Cytotoxicity assay		72 hrs		Cytotoxicity against human U87MG cells after 72 hrs by MTT assay, IC50 = 1.08 μM.	24012712
MKN45	Cytotoxicity assay		72 hrs		Cytotoxicity against human MKN45 cells after 72 hrs by MTT assay, IC50 = 0.032 μM.	24485123
A549	Cytotoxicity assay		72 hrs		Cytotoxicity against human A549 cells after 72 hrs by MTT assay, IC50 = 0.13 μM.	24485123
HT-29	Cytotoxicity assay		72 hrs		Cytotoxicity against human HT-29 cells after 72 hrs by MTT assay, IC50 = 0.16 μM.	24485123
H460	Cytotoxicity assay		72 hrs		Cytotoxicity against human H460 cells after 72 hrs by MTT assay, IC50 = 0.19 μM.	24485123
U87MG	Cytotoxicity assay		72 hrs		Cytotoxicity against human U87MG cells after 72 hrs by MTT assay, IC50 = 1.1 μM.	24485123
MKN45	Cytotoxicity assay		72 hrs		Cytotoxicity against human MKN45 cells after 72 hrs by MTT assay, IC50 = 0.032 μM.	24882675
HT-29	Cytotoxicity assay		72 hrs		Cytotoxicity against human HT-29 cells after 72 hrs by MTT assay, IC50 = 0.19 μM.	24882675
H460	Cytotoxicity assay		72 hrs		Cytotoxicity against human H460 cells after 72 hrs by MTT assay, IC50 = 0.21 μM.	24882675
MDA-MB-231	Cytotoxicity assay		72 hrs		Cytotoxicity against human MDA-MB-231 cells after 72 hrs by MTT assay, IC50 = 0.54 μM.	24882675
MKN45	Cytotoxicity assay		72 hrs		Cytotoxicity against human MKN45 cells assessed as inhibition of cell growth after 72 hrs by MTT assay, IC50 = 0.032 μM.	24996144
A549	Cytotoxicity assay		72 hrs		Cytotoxicity against human A549 cells assessed as inhibition of cell growth after 72 hrs by MTT assay, IC50 = 0.11 μM.	24996144
HT-29	Cytotoxicity assay		72 hrs		Cytotoxicity against human HT-29 cells assessed as inhibition of cell growth after 72 hrs by MTT assay, IC50 = 0.19 μM.	24996144
H460	Cytotoxicity assay		72 hrs		Cytotoxicity against human H460 cells assessed as inhibition of cell growth after 72 hrs by MTT assay, IC50 = 0.21 μM.	24996144
U87MG	Cytotoxicity assay		72 hrs		Cytotoxicity against human U87MG cells assessed as inhibition of cell growth after 72 hrs by MTT assay, IC50 = 1.08 μM.	24996144
MKN45	Antiproliferative assay		72 hrs		Antiproliferative activity against human MKN45 cells assessed as inhibition of cell growth after 72 hrs by MTT assay, IC50 = 0.032 μM.	25282672
A549	Antiproliferative assay		72 hrs		Antiproliferative activity against human A549 cells assessed as inhibition of cell growth after 72 hrs by MTT assay, IC50 = 0.12 μM.	25282672
HT-29	Antiproliferative assay		72 hrs		Antiproliferative activity against human HT-29 cells assessed as inhibition of cell growth after 72 hrs by MTT assay, IC50 = 0.19 μM.	25282672
H460	Antiproliferative assay		72 hrs		Antiproliferative activity against human H460 cells assessed as inhibition of cell growth after 72 hrs by MTT assay, IC50 = 0.21 μM.	25282672
U87MG	Antiproliferative assay		72 hrs		Antiproliferative activity against human U87MG cells assessed as inhibition of cell growth after 72 hrs by MTT assay, IC50 = 1.02 μM.	25282672
MKN45	Cytotoxicity assay		72 hrs		Cytotoxicity against human MKN45 cells after 72 hrs by MTT assay, IC50 = 0.032 μM.	25438768
A549	Cytotoxicity assay		72 hrs		Cytotoxicity against human A549 cells after 72 hrs by MTT assay, IC50 = 0.13 μM.	25438768
HT-29	Cytotoxicity assay		72 hrs		Cytotoxicity against human HT-29 cells after 72 hrs by MTT assay, IC50 = 0.16 μM.	25438768
H460	Cytotoxicity assay		72 hrs		Cytotoxicity against human H460 cells after 72 hrs by MTT assay, IC50 = 0.19 μM.	25438768
U87MG	Cytotoxicity assay		72 hrs		Cytotoxicity against human U87MG cells after 72 hrs by MTT assay, IC50 = 0.92 μM.	25438768
BA/F3	Function assay				Inhibition of ROS1 (unknown origin) expressed in mouse BA/F3 cells, IC50 = 0.01 μM.	25461320
HT-29	Cytotoxicity assay		72 hrs		Cytotoxicity against human HT-29 cells assessed as inhibition of cell proliferation after 72 hrs by MTT assay, IC50 = 0.032 μM.	26169763
MKN45	Cytotoxicity assay		72 hrs		Cytotoxicity against human MKN45 cells assessed as inhibition of cell proliferation after 72 hrs by MTT assay, IC50 = 0.12 μM.	26169763
A549	Cytotoxicity assay		72 hrs		Cytotoxicity against human A549 cells assessed as inhibition of cell proliferation after 72 hrs by MTT assay, IC50 = 0.19 μM.	26169763
H460	Cytotoxicity assay		72 hrs		Cytotoxicity against human H460 cells assessed as inhibition of cell proliferation after 72 hrs by MTT assay, IC50 = 0.21 μM.	26169763
BT474	Function assay				Inhibition of AXL in lapatinib-sensitive human BT474 cells, IC50 = 0.1 μM.	26555154
PC3	Cytotoxicity assay		72 hrs		Cytotoxicity against human PC3 cells after 72 hrs by MTT assay, IC50 = 0.39 μM.	26810712
A549	Cytotoxicity assay		72 hrs		Cytotoxicity against human A549 cells after 72 hrs by MTT assay, IC50 = 0.64 μM.	26810712
MCF7	Cytotoxicity assay		72 hrs		Cytotoxicity against human MCF7 cells after 72 hrs by MTT assay, IC50 = 9.47 μM.	26810712
MKN45	Cytotoxicity assay		72 hrs		Cytotoxicity against human MKN45 cells after 72 hrs by MTT assay, IC50 = 0.023 μM.	26897090
A549	Cytotoxicity assay		72 hrs		Cytotoxicity against human A549 cells after 72 hrs by MTT assay, IC50 = 0.17 μM.	26897090
HT-29	Cytotoxicity assay		72 hrs		Cytotoxicity against human HT-29 cells after 72 hrs by MTT assay, IC50 = 0.26 μM.	26897090
HT-29	Cytotoxicity assay		72 hrs		Cytotoxicity against human HT-29 cells assessed as reduction in cell growth after 72 hrs by MTT assay, IC50 = 0.26 μM.	26923692
A549	Cytotoxicity assay		72 hrs		Cytotoxicity against human A549 cells assessed as reduction in cell growth after 72 hrs by MTT assay, IC50 = 0.49 μM.	26923692
PC3	Cytotoxicity assay		72 hrs		Cytotoxicity against human PC3 cells assessed as reduction in cell growth after 72 hrs by MTT assay, IC50 = 0.89 μM.	26923692
MCF7	Cytotoxicity assay		72 hrs		Cytotoxicity against human MCF7 cells assessed as reduction in cell growth after 72 hrs by MTT assay, IC50 = 6.25 μM.	26923692
MKN45	Cytotoxicity assay		72 hrs		Cytotoxicity against human MKN45 cells assessed as cell growth inhibition after 72 hrs by MTT assay, IC50 = 0.032 μM.	26944614
A549	Cytotoxicity assay		72 hrs		Cytotoxicity against human A549 cells assessed as cell growth inhibition after 72 hrs by MTT assay, IC50 = 0.13 μM.	26944614
HT-29	Cytotoxicity assay		72 hrs		Cytotoxicity against human HT-29 cells assessed as cell growth inhibition after 72 hrs by MTT assay, IC50 = 0.16 μM.	26944614
H460	Cytotoxicity assay		72 hrs		Cytotoxicity against human H460 cells assessed as cell growth inhibition after 72 hrs by MTT assay, IC50 = 0.19 μM.	26944614
U87MG	Cytotoxicity assay		72 hrs		Cytotoxicity against human U87MG cells assessed as cell growth inhibition after 72 hrs by MTT assay, IC50 = 1.1 μM.	26944614
PC3	Cytotoxicity assay		72 hrs		Cytotoxicity against human PC3 cells after 72 hrs by MTT assay, IC50 = 0.39 μM.	26964675
A549	Cytotoxicity assay		72 hrs		Cytotoxicity against human A549 cells after 72 hrs by MTT assay, IC50 = 0.64 μM.	26964675
MCF7	Cytotoxicity assay		72 hrs		Cytotoxicity against human MCF7 cells after 72 hrs by MTT assay, IC50 = 9.47 μM.	26964675
BA/F3	Antiproliferative assay		72 hrs		Antiproliferative activity against mouse BA/F3 cells expressing TPR-Met after 72 hrs by CCK8 assay, IC50 = 0.0092 μM.	27068889
MKN45	Cytotoxicity assay		72 hrs		Cytotoxicity against human MKN45 cells measured after 72 hrs by MTT assay, IC50 = 0.032 μM.	27155466
A549	Cytotoxicity assay		72 hrs		Cytotoxicity against human A549 cells measured after 72 hrs by MTT assay, IC50 = 0.11 μM.	27155466
HT-29	Cytotoxicity assay		72 hrs		Cytotoxicity against human HT-29 cells measured after 72 hrs by MTT assay, IC50 = 0.19 μM.	27155466
H460	Cytotoxicity assay		72 hrs		Cytotoxicity against human H460 cells measured after 72 hrs by MTT assay, IC50 = 0.21 μM.	27155466
MKN45	Cytotoxicity assay				Cytotoxicity against human MKN45 cells, IC50 = 0.008 μM.	27187857
MKN45	Cytotoxicity assay		72 hrs		Cytotoxicity against human MKN45 cells after 72 hrs by MTT assay, IC50 = 0.023 μM.	27187857
HT-29	Cytotoxicity assay				Cytotoxicity against human HT-29 cells, IC50 = 0.029 μM.	27187857
A549	Cytotoxicity assay				Cytotoxicity against human A549 cells, IC50 = 0.165 μM.	27187857
HT-29	Cytotoxicity assay		72 hrs		Cytotoxicity against human HT-29 cells after 72 hrs by MTT assay, IC50 = 0.17 μM.	27187857
A549	Cytotoxicity assay		72 hrs		Cytotoxicity against human A549 cells after 72 hrs by MTT assay, IC50 = 0.26 μM.	27187857
MDA-MB-231	Cytotoxicity assay		72 hrs		Cytotoxicity against human MDA-MB-231 cells after 72 hrs by MTT assay, IC50 = 0.54 μM.	27187857
Sf9	Function assay		60 mins		Inhibition of NH2-terminal His-tagged MET kinase domain (1051 to 1348 residues) (unknown origin) expressed in baculovirus infected Sf9 insect cells preincubated for 60 mins followed by (poly(Glu, Tyr) 4:1) substrate addition for 2 to 4 hrs by luciferase-c, IC50 = 0.0004 μM.	27299736
MKN45	Cytotoxicity assay		72 hrs		Cytotoxicity against c-Met over-expressed human MKN45 cells assessed as cell growth inhibition after 72 hrs by MTT assay, IC50 = 0.032 μM.	27490023
A549	Cytotoxicity assay		72 hrs		Cytotoxicity against c-Met over-expressed human A549 cells assessed as cell growth inhibition after 72 hrs by MTT assay, IC50 = 0.14 μM.	27490023
HT-29	Cytotoxicity assay		72 hrs		Cytotoxicity against c-Met over-expressed human HT-29 cells assessed as cell growth inhibition after 72 hrs by MTT assay, IC50 = 0.19 μM.	27490023
H460	Cytotoxicity assay		72 hrs		Cytotoxicity against c-Met over-expressed human H460 cells assessed as cell growth inhibition after 72 hrs by MTT assay, IC50 = 0.21 μM.	27490023
A549	Cytotoxicity assay		72 hrs		Cytotoxicity against human A549 cells after 72 hrs by MTT assay, IC50 = 0.15 μM.	28011202
HT-29	Cytotoxicity assay		72 hrs		Cytotoxicity against human HT-29 cells after 72 hrs by MTT assay, IC50 = 0.25 μM.	28011202
MKN45	Cytotoxicity assay		72 hrs		Cytotoxicity against human MKN45 cells after 72 hrs by MTT assay, IC50 = 0.32 μM.	28011202
HT-29	Cytotoxicity assay		72 hrs		Cytotoxicity against human HT-29 cells after 72 hrs by MTT assay, IC50 = 0.25 μM.	28384549
H460	Cytotoxicity assay		72 hrs		Cytotoxicity against human H460 cells after 72 hrs by MTT assay, IC50 = 0.29 μM.	28384549
A549	Cytotoxicity assay		72 hrs		Cytotoxicity against human A549 cells after 72 hrs by MTT assay, IC50 = 0.36 μM.	28384549
U87MG	Cytotoxicity assay		72 hrs		Cytotoxicity against human U87MG cells after 72 hrs by MTT assay, IC50 = 0.96 μM.	28384549
MKN45	Antiproliferative assay		72 hrs		Antiproliferative activity against human MKN45 cells after 72 hrs by MTT assay, IC50 = 0.03 μM.	28716639
A549	Antiproliferative assay		72 hrs		Antiproliferative activity against human A549 cells after 72 hrs by MTT assay, IC50 = 0.15 μM.	28716639
HT-29	Antiproliferative assay		72 hrs		Antiproliferative activity against human HT-29 cells after 72 hrs by MTT assay, IC50 = 0.21 μM.	28716639
H460	Antiproliferative assay		72 hrs		Antiproliferative activity against human H460 cells after 72 hrs by MTT assay, IC50 = 0.22 μM.	28716639
U87MG	Antiproliferative assay		72 hrs		Antiproliferative activity against human U87MG cells after 72 hrs by MTT assay, IC50 = 0.96 μM.	28716639
HCC827	Function assay				Displacement of [3H]-cyclopamine from SMO V404M mutant in gefitinib resistant human HCC827 cells by scintillation counting, Ki = 0.0668 μM.	28787156
HCC827	Antiproliferative assay	72 hrs			Antiproliferative activity against gefitinib resistant EGFR-mutated human HCC827 cells after 72 hrs by MTT assay, IC50 = 0.5 μM.	28787156
HCC827	Antitumor assay	15 mg/kg			Antitumor activity against gefitinib resistant human HCC827 cells xenografted in balb/c athymic nu/nu mouse assessed as decrease in tumor size at 15 mg/kg/day, po	28787156
HCC827	Apoptosis assay	0.01 to 1 uM	72 hrs		Induction of apoptosis in gefitinib resistant human HCC827 cells at 0.01 to 1 uM after 72 hrs by annexin V-FITC-propidium iodide staining-based flow cytometry method relative to control	28787156
HCC827	Function assay	0.1 to 0.5 uM	72 hrs		Inhibition of MET phosphorylation at Tyr1234/1235 in gefitinib resistant human HCC827 cells at 0.1 to 0.5 uM after 72 hrs by Western blotting method	28787156
HCC827	Function assay	0.1 to 0.5 uM	72 hrs		Downregulation of SMO expression in gefitinib resistant human HCC827 cells at 0.1 to 0.5 uM after 72 hrs by Western blotting method	28787156
HCC827	Function assay	0.1 to 0.5 uM	72 hrs		Inhibition of MET in gefitinib resistant human HCC827 cells assessed as decrease in MAPK44/42 phosphorylation at Thr202/Tyr204 at 0.1 to 0.5 uM after 72 hrs by Western blotting method	28787156
HCC827	Function assay	0.1 to 0.5 uM	72 hrs		Inhibition of MET in gefitinib resistant human HCC827 cells assessed as decrease in AKT phosphorylation at Ser473 at 0.1 to 0.5 uM after 72 hrs by Western blotting method	28787156
HCC827	Function assay	0.1 to 0.5 uM	72 hrs		Inhibition of MET/SMO V404M mutant in gefitinib resistant human HCC827 cells assessed as decrease in vimentin expression at 0.1 to 0.5 uM after 72 hrs by Western blotting method	28787156
HCC827	Antitumor assay	20 mg/kg			Antitumor activity against gefitinib resistant human HCC827 cells xenografted in balb/c athymic nu/nu mouse assessed as decrease in tumor size at 20 mg/kg/day, po	28787156
HCC827	Antitumor assay	20 mg/kg			Antitumor activity against gefitinib resistant human HCC827 cells xenografted in balb/c athymic nu/nu mouse assessed as decrease in tumor size at 20 mg/kg/day, po in presence of gefitinib	28787156
HCC827	Antitumor assay	20 mg/kg			Antitumor activity against gefitinib resistant human HCC827 cells xenografted in balb/c athymic nu/nu mouse assessed as decrease in tumor size at 20 mg/kg/day, po in presence of osimertinib	28787156
PC3	Cytotoxicity assay		72 hrs		Cytotoxicity against human PC3 cells assessed as reduction in cell viability after 72 hrs by MTT assay, IC50 = 1.48 μM.	29107421
A549	Cytotoxicity assay		72 hrs		Cytotoxicity against human A549 cells assessed as reduction in cell viability after 72 hrs by MTT assay, IC50 = 1.74 μM.	29107421
HepG2	Cytotoxicity assay		72 hrs		Cytotoxicity against human HepG2 cells assessed as reduction in cell viability after 72 hrs by MTT assay, IC50 = 2.88 μM.	29107421
MCF7	Cytotoxicity assay		72 hrs		Cytotoxicity against human MCF7 cells assessed as reduction in cell viability after 72 hrs by MTT assay, IC50 = 3.92 μM.	29107421
HT-29	Antiproliferative assay		72 hrs		Antiproliferative activity against human HT-29 cells after 72 hrs by MTT assay, IC50 = 0.26 μM.	29197731
NCI-H460	Antiproliferative assay		72 hrs		Antiproliferative activity against human NCI-H460 cells after 72 hrs by MTT assay, IC50 = 0.28 μM.	29197731
A549	Antiproliferative assay		72 hrs		Antiproliferative activity against human A549 cells after 72 hrs by MTT assay, IC50 = 0.32 μM.	29197731
U87MG	Antiproliferative assay		72 hrs		Antiproliferative activity against human U87MG cells after 72 hrs by MTT assay, IC50 = 0.91 μM.	29197731
HepG2	Cytotoxicity assay		72 hrs		Cytotoxicity against human HepG2 cells after 72 hrs by MTT assay, IC50 = 2.27 μM.	29203143
MCF7	Cytotoxicity assay		72 hrs		Cytotoxicity against human MCF7 cells after 72 hrs by MTT assay, IC50 = 2.76 μM.	29203143
A549	Cytotoxicity assay		72 hrs		Cytotoxicity against human A549 cells after 72 hrs by MTT assay, IC50 = 3.13 μM.	29203143
PC3	Antiproliferative assay		72 hrs		Antiproliferative activity against human PC3 cells after 72 hrs by MTT assay, IC50 = 0.39 μM.	29331754
A549	Antiproliferative assay		72 hrs		Antiproliferative activity against human A549 cells after 72 hrs by MTT assay, IC50 = 0.64 μM.	29331754
MCF7	Antiproliferative assay		72 hrs		Antiproliferative activity against human MCF7 cells after 72 hrs by MTT assay, IC50 = 9.47 μM.	29331754
TC32	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for TC32 cells	29435139
DAOY	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for DAOY cells	29435139
SJ-GBM2	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SJ-GBM2 cells	29435139
A673	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for A673 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
BT-37	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-37 cells	29435139
NB-EBc1	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB-EBc1 cells	29435139
U-2 OS	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for U-2 OS cells	29435139
Saos-2	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Saos-2 cells	29435139
SK-N-SH	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-SH cells	29435139
NB1643	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB1643 cells	29435139
LAN-5	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for LAN-5 cells	29435139
BT-12	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-12 cells	29435139
Rh18	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh18 cells	29435139
OHS-50	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for OHS-50 cells	29435139
RD	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for RD cells	29435139
MG 63 (6-TG R)	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for MG 63 (6-TG R) cells	29435139
fibroblast cells	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for control Hh wild type fibroblast cells	29435139
Rh30	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh30 cells	29435139
Rh41	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh41 cells	29435139
NB1643	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for NB1643 cells	29435139
A673	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for A673 cells)	29435139
SK-N-MC	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for SK-N-MC cells	29435139
BT-12	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for BT-12 cells	29435139
LAN-5	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for LAN-5 cells	29435139
DAOY	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for DAOY cells	29435139
NB-EBc1	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for NB-EBc1 cells	29435139
SJ-GBM2	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for SJ-GBM2 cells	29435139
BT-37	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for BT-37 cells	29435139
TC32	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for TC32 cells	29435139
MG 63 (6-TG R)	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for MG 63 (6-TG R) cells	29435139
fibroblast cells	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for control Hh wild type fibroblast cells	29435139
U-2 OS	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for U-2 OS cells	29435139
Rh41	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for Rh41 cells	29435139
RD	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for RD cells	29435139
Rh18	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for Rh18 cells	29435139
Saos-2	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for Saos-2 cells	29435139
OHS-50	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for OHS-50 cells	29435139
SK-N-SH	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for SK-N-SH cells	29435139
A549	Antiproliferative assay		72 hrs		Antiproliferative activity against human A549 cells after 72 hrs by MTT assay, IC50 = 0.32 μM.	30216852
HepG2	Antiproliferative assay		72 hrs		Antiproliferative activity against human HepG2 cells after 72 hrs by MTT assay, IC50 = 0.48 μM.	30216852
MCF7	Antiproliferative assay		72 hrs		Antiproliferative activity against human MCF7 cells after 72 hrs by MTT assay, IC50 = 0.76 μM.	30216852
MKN45	Antiproliferative assay		72 hrs		Antiproliferative activity against human MKN45 cells after 72 hrs by MTT assay, IC50 = 0.0023 μM.	30248654
EBC1	Antiproliferative assay		72 hrs		Antiproliferative activity against human EBC1 cells after 72 hrs by MTT assay, IC50 = 0.0048 μM.	30248654
SNU5	Antiproliferative assay		72 hrs		Antiproliferative activity against human SNU5 cells after 72 hrs by MTT assay, IC50 = 0.0089 μM.	30248654
BAF3	Function assay		72 hrs		Inhibition of TPR-tagged met (unknown origin) expressed in mouse BAF3 cells assessed as inhibition of cell proliferation after 72 hrs by MTT assay, IC50 = 0.0092 μM.	30248654
NCI-H460	Antiproliferative assay		72 hrs		Antiproliferative activity against human NCI-H460 cells after 72 hrs by MTT assay, IC50 = 0.0396 μM.	30248654
MKN45	Cytotoxicity assay		72 hrs		Cytotoxicity in human MKN45 cells assessed as reduction in cell viability incubated for 72 hrs by MTT assay, IC50 = 0.041 μM.	31079967
NCI-H460	Cytotoxicity assay		72 hrs		Cytotoxicity in human NCI-H460 cells assessed as reduction in cell viability incubated for 72 hrs by MTT assay, IC50 = 0.18 μM.	31079967
HT-29	Cytotoxicity assay		72 hrs		Cytotoxicity in human HT-29 cells assessed as reduction in cell viability incubated for 72 hrs by MTT assay, IC50 = 0.22 μM.	31079967
MDA-MB-231	Cytotoxicity assay		72 hrs		Cytotoxicity in human MDA-MB-231 cells assessed as reduction in cell viability incubated for 72 hrs by MTT assay, IC50 = 0.52 μM.	31079967
sf21	Function assay		60 mins		Inhibition of wild type N-terminal NH-tagged and avi-tagged dephosphorylated c-MET (956 to 1390 residues) (unknown origin) expressed in sf21 cells using poly (Glu,Tyr) as substrate measured after 60 mins by ADP-Glo kinase assay, IC50 = 0.002512 μM.	31531204
sf21	Function assay		60 mins		Inhibition of N-terminal NH-tagged and avi-tagged dephosphorylated c-MET D1228V mutant (956 to 1390 residues) (unknown origin) expressed in sf21 cells using poly (Glu,Tyr) as substrate measured after 60 mins by ADP-Glo kinase assay, IC50 = 0.002512 μM.	31531204
NCI-H1993	Growth inhibition assay		3 days		Growth inhibition of CRISPR/Cas9 modified human NCI-H1993 cells harboring cMET D1228V mutant incubated for 3 days by cell titer-glo luminescent cell viability assay, GI50 = 0.05248 μM.	31531204
NCI-H1993	Growth inhibition assay		3 days		Growth inhibition of wild type human NCI-H1993 cells incubated for 3 days by cell titer-glo luminescent cell viability assay, GI50 = 0.06166 μM.	31531204
NCI-H1993	Function assay		4 hrs		Inhibition of c-Met phosphorylation at Tyr 1234/Tyr1235 residues in human NCI-H1993 cells incubated for 4 hrs by HTRF assay, IC50 = 0.2138 μM.	31531204
NCI-H1993	Function assay		4 hrs		Inhibition of c-MET D1228V mutant phosphorylation at Tyr1234/Tyr1235 residues in CRISPR/Cas9 modified human NCI-H1993 cells incubated for 4 hrs by HTRF assay, IC50 = 0.2138 μM.	31531204
NCI-H1993	Function assay	1 uM	4 hrs		Inhibition of c-MET D1228V mutant in CRISPR/Cas9 modified human NCI-H1993 cells assessed as reduction in AKT phosphorylation at 1 uM after 4 hrs by Western blot analysis	31531204
NCI-H1993	Function assay	1 uM	4 hrs		Inhibition of c-Met phosphorylation in human NCI-H1993 cells at 1 uM after 4 hrs by Western blot analysis	31531204
NCI-1993	Function assay	1 uM	4 hrs		Inhibition of c-MET in human NCI-1993 cells assessed as reduction in AKT phosphorylation at 1 uM after 4 hrs by Western blot analysis	31531204
NCI-H1993	Function assay	1 uM	4 hrs		Inhibition of c-Met D1228V mutant phosphorylation in CRISPR/Cas9 modified human NCI-H1993 cells at 1 uM after 4 hrs by Western blot analysis	31531204
sf21	Function assay				Binding affinity to wild type N-terminal NH-tagged and avi-tagged dephosphorylated c-MET (956 to 1390 residues) (unknown origin) expressed in sf21 cells by SPR analysis	31531204
sf21	Function assay				Binding affinity to N-terminal NH-tagged and avi-tagged dephosphorylated c-MET D1228V mutant (956 to 1390 residues) (unknown origin) expressed in sf21 cells by SPR analysis	31531204
A549	Antiproliferative assay		72 hrs		Antiproliferative activity against human A549 cells assessed as reduction in cell viability after 72 hrs by MTT assay, IC50 = 2.4 μM.	31546197
MCF7	Antiproliferative assay		72 hrs		Antiproliferative activity against human MCF7 cells assessed as reduction in cell viability after 72 hrs by MTT assay, IC50 = 2.4 μM.	31546197
HepG2	Antiproliferative assay		72 hrs		Antiproliferative activity against human HepG2 cells assessed as reduction in cell viability after 72 hrs by MTT assay, IC50 = 2.4 μM.	31546197
MKN45	Cytotoxicity assay		72 hrs		Cytotoxicity against human MKN45 cells assessed as reduction in cell viability incubated for 72 hrs by MTT assay, IC50 = 0.2 μM.	31629631
H460	Cytotoxicity assay		72 hrs		Cytotoxicity against human H460 cells assessed as reduction in cell viability incubated for 72 hrs by MTT assay, IC50 = 1.14 μM.	31629631
A549	Cytotoxicity assay		72 hrs		Cytotoxicity against human A549 cells assessed as reduction in cell viability incubated for 72 hrs by MTT assay, IC50 = 1.49 μM.	31629631
HT-29	Cytotoxicity assay		72 hrs		Cytotoxicity against human HT-29 cells assessed as reduction in cell viability incubated for 72 hrs by MTT assay, IC50 = 1.76 μM.	31629631
U87MG	Cytotoxicity assay		72 hrs		Cytotoxicity against human U87MG cells assessed as reduction in cell viability incubated for 72 hrs by MTT assay, IC50 = 2.17 μM.	31629631
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Informations chimiques, stockage et stabilité (Chemical Information, Storage & Stability)

Poids moléculaire	632.65	Formule	C₃₄H₃₄F₂N₄O₆	Stockage (À compter de la date de réception)	3 ans-20°Cpoudre
N° CAS	849217-64-7	Télécharger le SDF		Stockage des solutions mères	1 an-80°Cen solvant 1 mois-20°Cen solvant
Synonymes	GSK1363089, EXEL-2880, XL-880, GSK089			Smiles	COC1=CC2=C(C=CN=C2C=C1OCCCN3CCOCC3)OC4=C(C=C(C=C4)NC(=O)C5(CC5)C(=O)NC6=CC=C(C=C6)F)F

Solubilité (Solubility)

In vitro
Lot:

DMSO : 100 mg/mL (158.06 mM)
(Le DMSO contaminé par l'humidité peut réduire la solubilité. Utiliser du DMSO frais et anhydre.)

Water : Insoluble

Ethanol : Insoluble

Calculateur de molarité

Masse	Concentration	Volume	Poids moléculaire
=	×	×

Calculateur de dilution Calculateur de poids moléculaire

In vivo Lot:
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Clear solution	30%propylene glycol 1 5%Tween80 2 65%D5W Validé par les laboratoires Selleck. Si vous avez besoin d'ajustements à cette formulation, contactez notre équipe commerciale pour des tests personnalisés.	30.000mg/ml (47.42mM)	Taking the 1 mL working solution as an example, add 300 μL of 100 mg/ml clarified propylene glycol stock solution to 50 μL of Tween 80, mix evenly to clarify it; then continue to add 650 μL of D5W to adjust the volume to 1 mL. The mixed solution should be used immediately for optimal results.

Calculateur de formulation in vivo (Solution claire)

Étape 1 : Saisir les informations ci-dessous (Recommandé : Un animal supplémentaire pour tenir compte des pertes pendant l'expérience)

Dosage : mg/kg Poids moyen des animaux : g Volume de dosage par animal :μL Nombre d'animaux :

Étape 2 : Saisir la formulation in vivo (Ceci est seulement le calculateur, pas la formulation. Veuillez nous contacter d'abord s'il n'y a pas de formulation in vivo dans la section Solubilité.)

% DMSO + % + % Tween 80 + % ddH₂O

%DMSO+ %

Résultats du calcul :

Concentration de travail : mg/ml;

Méthode de préparation du liquide maître DMSO : mg médicament prédissous dans μL DMSO ( Concentration du liquide maître mg/mL, Veuillez nous contacter d'abord si la concentration dépasse la solubilité du DMSO du lot de médicament. )

Méthode de préparation de la formulation in vivo : Prendre μL DMSO liquide maître, puis ajouterμL PEG300, mélanger et clarifier, puis ajouterμL Tween 80, mélanger et clarifier, puis ajouter μL ddH₂O, mélanger et clarifier.

Méthode de préparation de la formulation in vivo : Prendre μL DMSO liquide maître, puis ajouter μL Huile de maïs, mélanger et clarifier.

Note : 1. Veuillez vous assurer que le liquide est clair avant d'ajouter le solvant suivant.
2. Assurez-vous d'ajouter le(s) solvant(s) dans l'ordre. Vous devez vous assurer que la solution obtenue, lors de l'ajout précédent, est une solution claire avant de procéder à l'ajout du solvant suivant. Des méthodes physiques telles que le vortex, les ultrasons ou le bain-marie chaud peuvent être utilisées pour faciliter la dissolution.

Mécanisme d'action (Mechanism of Action)

Targets/IC₅₀/Ki	Met (Cell-free assay) 0.4 nM KDR (Cell-free assay) 0.86 nM Tie-2 (Cell-free assay) 1.1 nM VEGFR3/FLT4 (Cell-free assay) 2.8 nM RON (Cell-free assay) 3 nM FLT3 (Cell-free assay) 3.6 nM PDGFRα (Cell-free assay) 3.6 nM Kit (Cell-free assay) 6.7 nM VEGFR1/FLT1 (Cell-free assay) 6.8 nM PDGFRβ (Cell-free assay) 9.6 nM
In vitro	XL880 inhibe les Protein Tyrosine Kinases de la famille des récepteurs HGF avec des valeurs d'IC50 de 0,4 nM pour Met et 3 nM pour Ron. XL880 inhibe également KDR, Flt-1 et Flt-4 avec des valeurs d'IC50 de 0,9 nM, 6,8 nM et 2,8 nM, respectivement. XL880 inhibe la croissance des colonies de cellules B16F10, A549 et HT29 avec des IC50 de 40 nM, 29 nM et 165 nM, respectivement. Une étude récente indique que XL880 affecte différemment la croissance cellulaire dans les lignées cellulaires de cancer gastrique MKN-45 et KATO-III. XL880 inhibe la phosphorylation de MET et des molécules de signalisation en aval dans les cellules MKN-45, tandis qu'il cible GFGR2 dans les cellules KATO-III.
Essai kinase	Dosage d'inhibition de la Kinase
Essai kinase	L'inhibition de la kinase est étudiée en utilisant l'un des trois formats d'essai : transfert de [³³P]phosphoryle, chimioluminescence couplée à la luciférase, ou technologie AlphaScreen Protein Tyrosine Kinase. Les IC50 sont calculées par analyse de régression non linéaire en utilisant XLFit. Essai de Kinase par Transfert de ³³P-Phosphoryle Les réactions sont effectuées dans des microplaques de 384 puits blanches, à fond clair et à forte liaison (Greiner, Monroe, NC). Les plaques sont recouvertes de 2 μg/puits de protéine ou de substrat peptidique dans un volume de 50 μL de tampon de revêtement contenant 40 μg/mL de substrat (poly(Glu, Tyr) 4:1, 22,5 mM Na2CO₃, 27,5 mM NaHCO₃, 50 mM NaCl et 3 mM NaN₃. Les plaques recouvertes sont lavées une fois avec 50 μL de tampon d'essai après une incubation d'une nuit à température ambiante (TA). Les composés d'essai et les enzymes sont combinés avec du ³³P-γ-ATP (3,3 μCi/nmol) dans un volume total de 20 μL. Le mélange réactionnel est incubé à TA pendant 2 heures et la réaction est arrêtée par aspiration. Les microplaques sont ensuite lavées 6 fois avec un tampon Tween-PBS (PBST) à 0,05%. Du liquide de scintillation (50 μL/puits) est ajouté et le ³³P incorporé est mesuré par spectrométrie de scintillation liquide à l'aide d'un compteur de scintillation MicroBeta. Essai de Chimioluminescence Couplée à la Luciférase Les réactions sont menées dans des microplaques blanches de 384 puits à liaison moyenne (Greiner). Dans une première étape, l'enzyme et le composé sont combinés et incubés pendant 60 minutes ; les réactions sont initiées par l'addition d'ATP et de substrat peptidique (poly(Glu, Tyr) 4:1) dans un volume final de 20 μL, et incubées à TA pendant 2 à 4 heures. Après la réaction de la kinase, une aliquote de 20 μL de Kinase Glo (Promega, Madison, WI) est ajoutée et le signal de luminescence est mesuré à l'aide d'un lecteur de plaque Victor. La consommation totale d'ATP est limitée à 50%. Essai de Protein Tyrosine Kinase AlphaScreen™ Des billes donneuses recouvertes de streptavidine et des billes accepteuses recouvertes d'anticorps anti-phosphotyrosine PY100 sont utilisées. Le poly(Glu,Tyr) 4:1 biotinylé est utilisé comme substrat. La phosphorylation du substrat est mesurée par l'addition de billes donneuses/accepteuses par luminescence après la formation du complexe bille donneuse-accepteuse. La kinase et les composés d'essai sont combinés et préincubés pendant 60 minutes, suivis de l'ajout d'ATP et de poly(Glu, Tyr) biotinylé dans un volume total de 20 μL dans des microplaques blanches de 384 puits à liaison moyenne (Greiner). Les mélanges réactionnels sont incubés pendant 1 heure à température ambiante. Les réactions sont stoppées par l'ajout de 10 μL d'une suspension de billes AlphaScreen de 15-30 μg/mL contenant 75 mM Hepes, pH 7,4, 300 mM NaCl, 120 mM EDTA, 0,3% BSA et 0,03% Tween-20. Après 2 à 16 heures d'incubation à température ambiante, les plaques sont lues à l'aide d'un lecteur AlphaQuest.
In vivo	Une dose unique de 100 mg/kg de XL880 par gavage oral entraîne une inhibition substantielle de la phosphorylation de Met tumorale B16F10 et de la phosphorylation des récepteurs induite par le ligand (par exemple, HGF ou VEGF) de Met dans le foie et de Flk-1/KDR dans le poumon, qui ont toutes deux persisté pendant 24 heures. Le traitement par XL880 (30-100 mg/kg, une fois par jour, gavage oral) entraîne une réduction de la charge tumorale. La charge tumorale de surface pulmonaire est réduite de 50 % et 58 % après traitement avec 30 et 100 mg/kg de XL880, respectivement. Le traitement par XL880 chez des souris porteuses de tumeurs solides B16F10 entraîne également une inhibition dose-dépendante de la croissance tumorale de 64 % et 87 % à 30 et 100 mg/kg, respectivement. Pour les deux études, l'administration de XL880 a été bien tolérée sans perte de poids corporel significative. XL880 est développé pour cibler la signalisation anormale de HGF via Met et cibler simultanément plusieurs Protein Tyrosine Kinases de récepteurs impliqués dans l'angiogenèse tumorale. XL880 a provoqué une hémorragie et une nécrose tumorale dans des xénogreffes humaines en 2 à 4 heures, et la nécrose tumorale maximale a été observée à 96 heures (après cinq doses quotidiennes), entraînant une régression complète.
Références	[1] http://www.ncbi.nlm.nih.gov/pubmed?term=19808973%20 [2] https://pubmed.ncbi.nlm.nih.gov/21655918/ [3] https://pubmed.ncbi.nlm.nih.gov/20472683/

Applications (Applications)

Méthodes	Biomarqueurs	Images	PMID
Western blot	pROS1 / tROS1 / pSHP2 / pERK / ERK p-MDM2 / p53 / PUMA p-Met / Met / p-Akt / Akt		24218589
Growth inhibition assay	Cell viability		29854314

Informations sur l'essai clinique (Clinical Trial Information)

(données du https://clinicaltrials.gov, mis à jour le 2024-05-22)

Numéro NCT	Recrutement	Conditions	Promoteur/Collaborateurs	Date de début	Phases
NCT00920192	Completed	Carcinoma Hepatocellular	GlaxoSmithKline	August 12 2009	Phase 1
NCT00742261	Completed	Solid Tumours	GlaxoSmithKline	August 11 2008	Phase 1
NCT00725764	Completed	Neoplasms Head and Neck	GlaxoSmithKline	August 27 2007	Phase 2
NCT00725712	Completed	Neoplasms Gastrointestinal Tract	GlaxoSmithKline	March 31 2007	Phase 2
NCT00743067	Completed	Solid Tumours	GlaxoSmithKline	August 9 2006	Phase 1

C1=C0/X	C1:	LOG(C1):
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C4=C3/X	C4:	LOG(C4):
C5=C4/X	C5:	LOG(C5):
C6=C5/X	C6:	LOG(C6):
C7=C6/X	C7:	LOG(C7):
C8=C7/X	C8:	LOG(C8):