Foretinib | XL880 | MET/VEGFR2/KDR Inhibitor | AmBeed-信号通路专用抑制剂

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产品名称	VEGFR1 ↓ ↑	VEGFR2 ↓ ↑	VEGFR3 ↓ ↑	其他靶点	纯度
Motesanib Diphosphate	++++ VEGFR1, IC50: 2 nM	++++ VEGFR2/Flk1, IC50: 3 nM VEGFR2, IC50: 3 nM	+++ VEGFR3, IC50: 6 nM	RET,PDGFR	97%
Tivozanib	++ VEGFR1, IC50: 30 nM	+++ VEGFR2, IC50: 6.5 nM	++ VEGFR3, IC50: 15 nM		99%+
Brivanib	+ VEGFR1, IC50: 380 nM	++ Flk1, IC50: 25 nM VEGFR2, IC50: 25 nM			99%+
Regorafenib	+++ VEGFR1, IC50: 13 nM	+++ VEGFR2, IC50: 4.2 nM	+ VEGFR3, IC50: 46 nM	RET	98%
Pazopanib	+++ VEGFR1, IC50: 10 nM	++ VEGFR2, IC50: 30 nM	+ VEGFR3, IC50: 47 nM	c-Kit,PDGFR,FGFR	99%
Sitravatinib	+++ VEGFR1 (FLT1), IC50: 6 nM	+++ VEGFR2 (KDR), IC50: 5 nM	++++ VEGFR3 (FLT4), IC50: 2 nM		99%+
Foretinib	+++ VEGFR1/FLT1, IC50: 6.8 nM	++++ KDR, IC50: 0.86 nM	++++ VEGFR3/FLT4, IC50: 2.8 nM	Tie-2	99%+
MGCD-265 analog	++++ VEGFR1, IC50: 3 nM	++++ VEGFR2, IC50: 3 nM	++++ VEGFR3, IC50: 4 nM	Tie-2	99%+
Lactate	+++ VEGFR1/FLT1, IC50: 10 nM	+++ VEGFR2/Flk1, IC50: 13 nM	+++ VEGFR3/FLT4, IC50: 8 nM	c-Kit,FLT3	85%
AEE788	+ FLT1, IC50: 59 nM	+ KDR, IC50: 77 nM		EGFR	98+%
Linifanib	++++ VEGFR1/FLT1, IC50: 3 nM	++++ VEGFR2/KDR, IC50: 4 nM	+ VEGFR3/FLT4, IC50: 190 nM	FLT3	99%+
Vatalanib 2HCl	+ VEGFR1/FLT1, IC50: 77 nM	++ VEGFR2/Flk1, IC50: 270 nM VEGFR2/KDR, IC50: 37 nM	+ VEGFR3/FLT4, IC50: 660 nM	c-Kit,c-Fms/CSF1R	99%+
Axitinib	++++ VEGFR1/FLT1, IC50: 0.1 nM	++++ VEGFR2/Flk1, IC50: 0.18 nM VEGFR2/KDR, IC50: 0.2 nM			98%
Dovitinib	+++ VEGFR1/FLT1, IC50: 10 nM	+++ VEGFR2/Flk1, IC50: 13 nM	+++ VEGFR3/FLT4, IC50: 8 nM	c-Kit,FLT3	99%+
ZM 306416	+ VEGFR1, IC50: 0.33 μM			Src	99%+
KRN-633	+ VEGFR1, IC50: 170 nM	+ VEGFR2, IC50: 160 nM	+ VEGFR3, IC50: 125 nM	BTK,c-Kit	98%
OSI-930	+++ FLT1, IC50: 8 nM	+++ KDR, IC50: 9 nM			99%+
Lenvatinib	++ VEGFR1/FLT1, IC50: 22 nM	++++ VEGFR2/KDR, IC50: 4.0 nM	+++ VEGFR3/FLT4, IC50: 5.2 nM		98%
NVP-BAW2881	+ hVEGFR1, IC50: 820 nM	+++ hVEGFR2, IC50: 9 nM mVEGF2, IC50: 165 nM	+ hVEGFR3, IC50: 420 nM		99%
Cediranib	+++ VEGFR1/FLT1, IC50: 5 nM	++++ VEGFR2/KDR, IC50: 0.5 nM		c-Kit	99%+
Nintedanib	++ VEGFR1, IC50: 34 nM	+++ VEGFR2, IC50: 13 nM	+++ VEGFR3, IC50: 13 nM	FLT3	99+%
BMS-794833		++ VEGFR2, IC50: 15 nM			99%+
SKLB1002		++ VEGFR2, IC50: 32 nM			99%
Cabozantinib S-malate		++++ VEGFR2/KDR, IC50: 0.035 nM			99+%
Ki8751		++++ VEGFR2, IC50: 0.9 nM		c-Kit	99%
SU 5402		++ VEGFR2, IC50: 20 nM			98%
Apatinib mesylate		++++ VEGFR2, IC50: 1 nM		RET	98+%
Ponatinib		++++ VEGFR2, IC50: 1.5 nM			98%
LY2874455		+++ VEGFR2, IC50: 7 nM			99%+
ZM323881 HCl		++++ VEGFR2, IC50: <2 nM			98%
AZD2932		+++ VEGFR-2, IC50: 8 nM		c-Kit	99%
Cabozantinib		++++ VEGFR2/KDR, IC50: 0.035 nM			98%
Sorafenib		++ VEGFR2/Flk1, IC50: 90 nM VEGFR2, IC50: 90 nM			99%
CYC-116		++ VEGFR2, Ki: 44 nM		FLT3	99%+
Golvatinib		++ VEGFR2, IC50: 16 nM			99%+
Sunitinib		+ VEGFR2 , IC50: 80 nM		FLT3	98%
RAF265		++ VEGFR2, EC50: 30 nM			99%+
PD173074					99%+
BFH772		++++ VEGFR2, IC50: 3 nM			98%
Semaxinib		+ VEGFR2/Flk1, IC50: 1.23 μM			98%
Vandetanib		++ VEGFR2, IC50: 40 nM	+ VEGFR3, IC50: 110 nM	EGFR	99%
SAR131675			++ VEGFR3, IC50: 23 nM		99%+
ENMD-2076		+ VEGFR2/KDR, IC50: 58.2 nM	++ VEGFR3/FLT4, IC50: 15.9 nM	RET,FLT3	98%
Telatinib		+++ VEGFR2, IC50: 6 nM	++++ VEGFR3, IC50: 4 nM	c-Kit	99%+
1. 鼠标悬停在“+”上可以显示相关IC50的具体数值。"+"越多，抑制作用越强。2. "✔"表示该化合物对相应的亚型有抑制作用，但抑制强度暂时没有相关数据。

靶点	VEGFR1 VEGFR1/FLT1, IC50:6.8 nM VEGFR3 VEGFR3/FLT4, IC50:2.8 nM VEGFR2 KDR, IC50:0.86 nM
描述	The overexpression and activation of the Met receptor and its ligand HGF (hepatocyte growth factor) are associated with a wide variety of human malignancies. Meanwhile, it is found that VEGFRs can cooperate with Met to induce tumor invasion and vascularization. Foretinib is a multiple RTKs inhibitor with IC50 values of 0.4, 0.9/2.8 and 3nM for Met, VEGFR2/3 and Ron, less potent to Tie-2, Flt-3, PDGFRα, KIT, VEGFR1, PDGFRβ with IC50 values of 1.1nM, 3.6nM, 3.6nM, 6.7nM, 6.8nM and 9.6nM, with almost no inhibition of FGFR1 or EGFR (measured by in vitro kinase assay). Potent inhibition of p-Met by Foretinib with IC50 values of 23 and 21nM in PC-3 and B16F10 cells, as well as the suppression of p-ERK and p-VEGFR2 induced by VEGF with IC50 of 16nM in HUVECs can be observed, suggesting the cellular RTKs inhibition. Foretinib can block HGF-induced migration with IC50 value of 44nM, as well as inhibit the anchorage-independent tumor cell colony growth of B16F10 cells with IC50 of 40nM. A further study on Inhibition of endothelial tubule formation and migration by Foretinib showed that Foretinib at concentration of 5nM or higher can both inhibit VEGF-induced tubule formation and block VEGF- or HGF-stimulated migration of HMVEC-L cells. Once daily oral administration of Foretinib at dose of 30 and 100mg/kg reduced lung surface tumor burden by 50% and 58%, respectively, in mice intravenously implanted B16F10 cells. Similarly, Foretinib at dose of 30 and 100mg/kg resulted in tumor growth inhibition of 64% and 87%, respectively, in mice bearing B16F10 solid tumors^[1].
作用机制	Foretinib is an ATP-competitive inhibitor of HGFR and VEGFR.^[1]

Cell Line ccRCC organoids MDA-MB-231 cells MCF7A02 MCF10A CDH1-/- MV4-11 MOLM13 HCC1937 sensory neurons motor neurons HDQP1 ES2 OVCA cells MKN-45 KATO-III SNU-1 sympathetic neurons MV4-11 cells MOLM13 cells	Concentration	Treated Time	Description	References
ccRCC organoids	10 μM	72 h	To evaluate the effect of Foretinib on ccRCC organoids, results showed that Foretinib consistently induced Cleaved-Caspase 3 activation, indicating apoptosis induction	Cell Death Dis. 2019 Feb 27;10(3):201.
MDA-MB-231 cells	1 μM	18 h	To evaluate the effect of Foretinib in combination with PARP inhibitors on DNA damage in MDA-MB-231 cells, showing that the combination significantly increased γ-H2AX foci formation.	Nat Med. 2016 Feb;22(2):194-201.
MCF7A02	1 μM	6 days	To validate the synthetic lethality of Foretinib in E-cadherin defective cells, results showed that E-cadherin defective cells were more sensitive to Foretinib.	Cancer Discov. 2018 Apr;8(4):498-515.
MCF10A CDH1-/-	1 μM	6 days	To validate the synthetic lethality of Foretinib in E-cadherin defective cells, results showed that E-cadherin defective cells were more sensitive to Foretinib.	Cancer Discov. 2018 Apr;8(4):498-515.
MV4-11	0.16 nM	48 h	Inhibited the growth of FLT3-ITD mutant cells	Cancer Res. 2024 Mar 15;84(6):905-918.
MOLM13	0.89 nM	48 h	Inhibited the growth of FLT3-ITD mutant cells	Cancer Res. 2024 Mar 15;84(6):905-918.
HCC1937	1 μM	5 days	To test the effect of Foretinib in combination with afatinib, results showed that the combination treatment significantly inhibited cell growth.	Ther Adv Med Oncol. 2020 Jan 28;12:1758835919897546.
sensory neurons	500 nM	48 h	Foretinib rescued sensory neurons from degeneration	J Cell Biol. 2017 Nov 6;216(11):3655-3675.
motor neurons	500 nM	9 days	Foretinib significantly promoted the survival of motor neurons	J Cell Biol. 2017 Nov 6;216(11):3655-3675.
HDQP1	1 μM	5 days	To test the effect of Foretinib in combination with afatinib, results showed that the combination treatment significantly inhibited cell growth.	Ther Adv Med Oncol. 2020 Jan 28;12:1758835919897546.
ES2 OVCA cells	10 µM	72 h	To test the cytotoxicity of Foretinib in combination with Trametinib on ES2 cells. Results showed that the combination significantly enhanced cytotoxicity	Sci Adv. 2020 May 22;6(21):eaaz8521.
MKN-45	10 nM, 100 nM, 1 μM	72 h	Evaluate the effect of Foretinib on the viability of MKN-45 cells, showing reductions in cell viability of 5.4%, 73.7%, and 85.3% at concentrations of 10 nM, 100 nM, and 1 μM, respectively.	J Cell Mol Med. 2021 Jun;25(11):4950-4961.
KATO-III	10 nM, 100 nM, 1 μM	72 h	Evaluate the effect of Foretinib on the viability of KATO-III cells, showing reductions in cell viability of 1.2%, 51%, and 78.5% at concentrations of 10 nM, 100 nM, and 1 μM, respectively.	J Cell Mol Med. 2021 Jun;25(11):4950-4961.
SNU-1	1 nM, 10 nM, 100 nM, 1 μM	72 h	Evaluate the effect of Foretinib on the viability of SNU-1 cells, showing no significant inhibitory effect at 1 nM, 10 nM, or 100 nM, but a 68.1% reduction in cell viability at 1 μM concentration.	J Cell Mol Med. 2021 Jun;25(11):4950-4961.
sympathetic neurons	500 nM	16 h	Foretinib almost completely rescued neurons from degeneration	J Cell Biol. 2017 Nov 6;216(11):3655-3675.
MV4-11 cells	0.16 nM	48 h	To evaluate the growth inhibitory effect of Foretinib on MV4-11 cells carrying FLT3-ITD mutations, results showed that Foretinib effectively inhibited the growth of MV4-11 cells with an IC50 value of 0.16 nM	Cancer Res. 2024 Mar 15;84(6):905-918.
MOLM13 cells	0.89 nM	48 h	To evaluate the growth inhibitory effect of Foretinib on MOLM13 cells carrying FLT3-ITD mutations, results showed that Foretinib effectively inhibited the growth of MOLM13 cells with an IC50 value of 0.89 nM	Cancer Res. 2024 Mar 15;84(6):905-918.

Species Nude mice Mice Mice Nu/nu mice Mouse NOD/SCID mice Mice	Animal Model MDA-MB-231 xenograft model K14cre;Cdh1F/F;Trp53F/F (KEP) model FLT3-ITD AML mouse model ES2 xenograft model Medulloblastoma model Subcutaneous and peritoneal dissemination xenograft models Sciatic nerve crush model	Administration	Dosage	Frequency	Description	References
Nude mice	MDA-MB-231 xenograft model	Oral	5 mg/kg	5 times per week for 26 days	To evaluate the effect of Foretinib in combination with PARP inhibitors on tumor growth in MDA-MB-231 xenograft models, showing that the combination significantly inhibited tumor growth.	Nat Med. 2016 Feb;22(2):194-201.
Mice	K14cre;Cdh1F/F;Trp53F/F (KEP) model	Oral	25 mg/kg or 50 mg/kg	Every other day for 28 days	To evaluate the anti-tumour effects of Foretinib in E-cadherin defective tumours, results showed that Foretinib significantly inhibited tumour growth and extended mouse survival.	Cancer Discov. 2018 Apr;8(4):498-515.
Mice	FLT3-ITD AML mouse model	Oral	15 mg/kg	Once daily for 14 days	Foretinib significantly extended the survival of FLT3-ITD AML mice	Cancer Res. 2024 Mar 15;84(6):905-918.
Nu/nu mice	ES2 xenograft model	Tail vein injection	10 mg/kg	Every 4 days, until the experimental end point	To evaluate the effect of NanoFore combined with trametinib on tumor progression, results showed that the combination therapy significantly extended the survival of mice	Sci Adv. 2020 May 22;6(21):eaaz8521.
Mouse	Medulloblastoma model	Continuous osmotic pump infusion into the cerebrospinal fluid	6 mg/kg	28 days, 0.25 μl per hour	To study the anti-tumor effects and resistance mechanisms of Foretinib in a medulloblastoma model	Acta Neuropathol Commun. 2018 Dec 27;6(1):146
NOD/SCID mice	Subcutaneous and peritoneal dissemination xenograft models	Intraperitoneal injection	30 mg/kg	3 times per week for 2 weeks	Evaluate the antitumor effects of Foretinib in gastric cancer models, showing that Foretinib monotherapy significantly inhibited tumor growth and exhibited additive effects when combined with nanoparticle paclitaxel.	J Cell Mol Med. 2021 Jun;25(11):4950-4961.
Mice	Sciatic nerve crush model	Oral	100 mg/kg	4 times over 4 days	Foretinib delayed Wallerian degeneration after sciatic nerve crush	J Cell Biol. 2017 Nov 6;216(11):3655-3675.

NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
NCT01068587	Lung Cancer	Phase 1 Phase 2	Completed	-	Canada, British Columbia ... 展开 >> BCCA - Vancouver Cancer Centre Vancouver, British Columbia, Canada, V5Z 4E6 Canada, Ontario Juravinski Cancer Centre at Hamilton Health Sciences Hamilton, Ontario, Canada, L8V 5C2 Ottawa Health Research Institute - General Division Ottawa, Ontario, Canada, K1H 8L6 Univ. Health Network-Princess Margaret Hospital Toronto, Ontario, Canada, M5G 2M9 收起 <<
NCT00725712	Neoplasms, Gastrointestinal Tr... 展开 >>act 收起 <<	Phase 2	Completed	-	United States, Alabama ... 展开 >> GSK Investigational Site Birmingham, Alabama, United States, 35294 United States, Arizona GSK Investigational Site Scottsdale, Arizona, United States, 85258 United States, California GSK Investigational Site Los Angeles, California, United States, 90024 GSK Investigational Site Stanford, California, United States, 94305 United States, District of Columbia GSK Investigational Site Washington, D.C., District of Columbia, United States, 20007 United States, Georgia GSK Investigational Site Atlanta, Georgia, United States, 30309 United States, Illinois GSK Investigational Site Chicago, Illinois, United States, 60637 United States, Massachusetts GSK Investigational Site Boston, Massachusetts, United States, 02114 United States, Michigan GSK Investigational Site Detroit, Michigan, United States, 48201 United States, Montana GSK Investigational Site Billings, Montana, United States, 59101 United States, New Mexico GSK Investigational Site Albuquerque, New Mexico, United States, 87131 United States, New York GSK Investigational Site New York, New York, United States, 10016 GSK Investigational Site New York, New York, United States, 10021 United States, North Carolina GSK Investigational Site Durham, North Carolina, United States, 27710 United States, Oregon GSK Investigational Site Portland, Oregon, United States, 97239 United States, Texas GSK Investigational Site Austin, Texas, United States, 78705 United States, Wisconsin GSK Investigational Site Madison, Wisconsin, United States, 53792 收起 <<
NCT00725712	-		Completed	-	-

CAS号	849217-64-7
分子式	C₃₄H₃₄F₂N₄O₆
分子量	632.65
SMILES Code	O=C(NC1=CC=C(F)C=C1)C2(C(=O)NC3=CC=C(OC=4C=CN=C5C=C(OCCCN6CCOCC6)C(OC)=CC54)C(F)=C3)CC2
MDL No.	MFCD16038048

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别名	XL880; GSK1363089; EXEL-2880; GSK089
运输	蓝冰
InChI Key	CXQHYVUVSFXTMY-UHFFFAOYSA-N
Pubchem ID	42642645

VEGFR1	VEGFR1/FLT1, IC50:6.8 nM
VEGFR3	VEGFR3/FLT4, IC50:2.8 nM
VEGFR2	KDR, IC50:0.86 nM

A172	100/300/900 nM	Function Assay	1 h	inhibits the phosphorylation of MerTK	24658326
A172	100/300/900 nM	Function Assay	1 h	inhibits the activity of Axl, Tyro3	24658326
A172	100/300/900 nM	Function Assay	1 h	decreases Akt phosphorylation in a concentration dependent manner	24658326
A172	100/300/900 nM	Growth Inhibition Assay	48 h	reduces cell survival at 900 nM significantly	24658326
A172	100/300/900 nM	Function Assay	24 h	abrogates migration and invasion of glioma cells in a dose dependent manner	24658326
Ba/F3	0.0001-10 μM	Cell Viability Assay	72 h	inhibits cell growth in a dose dependent manner	24218589
Daoy	0.5/1/2.5 μM	Function Assay	24 h	inhibits the HGF-induced cMET pathway activation	25391241
Daoy	0.5/1/2.5 μM	Function Assay	24 h	inhibits HGF-mediated migration and invasion	25391241
Daoy	1 μM	Apoptosis Assay	24 h	induces apoptosis	25391241
Daoy	0.5/1/2.5 μM	Growth Inhibition Assay	24-96 h	inhibits cell growth in a dose dependent manner	25391241
H1573		Growth Inhibition Assay		IC50=1.62 ± 0.05 μM	21252284
H1648		Growth Inhibition Assay		IC50=1.28 ±0.12 μM	21252284
H1975		Growth Inhibition Assay		IC50=1.39 ± 0.33 μM	21252284
H596		Growth Inhibition Assay		IC50=1.21 ± 0.17 μM	21252284
H69		Growth Inhibition Assay		IC50=1.18 ± 0.08 μM	21252284
HCC78	0.01-10 μM	Cell Viability Assay	72 h	inhibits cell growth in a dose dependent manner	24218589
HN5		Growth Inhibition Assay		IC50=0.65 ± 0.26 μM	21252284
HOP92		Growth Inhibition Assay		IC50=0.81 ± 0.29 μM	21252284
KATO-III	0.01-10 μM	Growth Inhibition Assay	5 d	IC50=30 nM	21655918
KATO-III	1 μM	Function Assay	24 h	inhibits phosphorylation of MET, Akt, and ERK1/2 in MKN-45	21655918
MKN-45	0.01-10 μM	Growth Inhibition Assay	5 d	IC50=8 nM	21655918
MKN-45	1 μM	Function Assay	24 h	inhibits phosphorylation of MET, Akt, and ERK1/2 in MKN-45	21655918
ONS76	0.5/1/2.5 μM	Function Assay	24 h	inhibits the HGF-induced cMET pathway activation	25391241
ONS76	0.5/1/2.5 μM	Function Assay	24 h	inhibits HGF-mediated migration and invasion	25391241
SCC15		Growth Inhibition Assay		IC50=0.63 ± 0.04 μM	21252284
SF188	100/300/900 nM	Function Assay	1 h	inhibits the phosphorylation of MerTK	24658326
SF188	100/300/900 nM	Function Assay	1 h	inhibits the activity of Axl, Tyro3	24658326
SF188	100/300/900 nM	Function Assay	1 h	decreases Akt phosphorylation in a concentration dependent manner	24658326
SF188	100/300/900 nM	Function Assay	28 h	induces PARP cleavage	24658326
SF188	100/300/900 nM	Growth Inhibition Assay	48 h	reduces cell survival at 900 nM significantly	24658326
SF188	100/300/900 nM	Function Assay	24 h	abrogates migration and invasion of glioma cells in a dose dependent manner	24658326
SK-HEP1	0.25-1.5 μM	Cell Viability Assay	24 h	inhibits cell growth in a dose dependent manner	22187171
SK-HEP2	1 μM	Function Assay	24 h	blocks HGF-induced cell motility	22187171
SK-HEP2	1 μM	Function Assay	24 h	causes G2/M phase arrest with reduction in the G0/G1 and S phases	22187171
U251	100/300/900 nM	Function Assay	1 h	inhibits the phosphorylation of MerTK	24658326
U251	100/300/900 nM	Function Assay	1 h	inhibits the activity of Axl, Tyro3	24658326
U251	100/300/900 nM	Function Assay	1 h	decreases Akt phosphorylation in a concentration dependent manner	24658326
U251	100/300/900 nM	Function Assay	28 h	induces PARP cleavage	24658326
U251	100/300/900 nM	Growth Inhibition Assay	48 h	reduces cell survival at 900 nM significantly	24658326
U251	100/300/900 nM	Function Assay	24 h	abrogates migration and invasion of glioma cells in a dose dependent manner	24658326

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