Name: foretinib
Brand: BOC Sciences
Price: 298 USD
Availability: MadeToOrder

Synonyms

XL880; XL 880; XL-880; GSK1363089; GSK 1363089; GSK-1363089; GSK089; EXEL2880; Foretinib.

InChI Key

CXQHYVUVSFXTMY-UHFFFAOYSA-N

InChI

InChI=1S/C34H34F2N4O6/c1-43-30-20-25-27(21-31(30)45-16-2-13-40-14-17-44-18-15-40)37-12-9-28(25)46-29-8-7-24(19-26(29)36)39-33(42)34(10-11-34)32(41)38-23-5-3-22(35)4-6-23/h3-9,12,19-21H,2,10-11,13-18H2,1H3,(H,38,41)(H,39,42)

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

Mechanism

Target: This ligand targets MET, VEGFR2/KDR, RON/MST1R, AXL, TIE2/TEK, and related receptor tyrosine kinases in biochemical or cellular target-engagement studies.

Mechanism of Action: Used as the target-protein recognition element, this ligand provides the binding interface for MET, VEGFR2/KDR, RON/MST1R, AXL, TIE2/TEK, and related receptor tyrosine kinases. In PROTAC design, a derivatizable position on the ligand can be connected through an optimized linker to an E3 ligase ligand, such as a CRBN, VHL, or IAP recruiter, while preserving productive target engagement. The resulting bifunctional molecule brings MET into proximity with the recruited E3 ligase, enabling ternary-complex formation. If the complex has favorable geometry and residence time, target lysine ubiquitination is promoted, leading to proteasome-dependent degradation in experimental systems.

Applications

• PROTAC Ligand for MET: Foretinib can serve as a high-affinity kinase-binding ligand in PROTAC designs targeting MET (and related kinases). By recruiting an E3 ligase through a suitable linker, foretinib-based chimeras may drive ubiquitination and degradation of MET, enabling functional interrogation of MET-dependent signaling and resistance mechanisms in cancer-relevant models.

• EGFR/MET Degradation Studies: Because foretinib exhibits activity across MET and EGFR family kinases, it is useful for PROTAC strategies aimed at degrading EGFR/MET signaling nodes. Such constructs can help disentangle pathway crosstalk, quantify degradation-driven versus inhibition-driven phenotypes, and map how receptor tyrosine kinase abundance influences downstream transcriptional programs.

• Resistance Mechanism Probing: Foretinib-derived PROTACs can be applied to study how targeted protein degradation overcomes resistance to kinase inhibitors. Comparing degradation kinetics and pathway suppression against conventional foretinib treatment can reveal whether loss of the target protein, rather than catalytic blockade alone, restores sensitivity or bypasses compensatory signaling.

• Linker and E3 Ligase Optimization: Foretinib-based ligands are well-suited for systematic PROTAC optimization, including linker length/composition and E3 ligase selection. Tuning these parameters can modulate ternary complex formation, ubiquitination efficiency, and degradation potency, supporting mechanistic studies of how molecular geometry controls selectivity and on-target turnover.

1.Molecular Changes Associated with Acquired Resistance to Crizotinib in ROS1-Rearranged Non-Small Cell Lung Cancer.

Song A;Kim TM;Kim DW;Kim S;Keam B;Lee SH;Heo DS Clin Cancer Res. 2015 May 15;21(10):2379-87. doi: 10.1158/1078-0432.CCR-14-1350. Epub 2015 Feb 16.

PURPOSE: ;Although ROS1-rearranged non-small cell lung cancer (NSCLC) is sensitive to crizotinib, development of resistance is inevitable. Here, we identified molecular alterations in crizotinib-resistant tumors from two NSCLC patients with the CD74-ROS1 rearrangement, and in HCC78 cells harboring SLC34A2-ROS1 that showed resistance to crizotinib (HCC78CR cells).;EXPERIMENTAL DESIGN: ;ROS1 kinase domain mutations were examined in fresh tumor tissues from two NSCLC patients and HCC78CR1-3 cells by direct sequencing. Ba/F3 cells expressing ROS1 secondary mutations were constructed to evaluate resistance to crizotinib. An upregulated pathway was identified using phospho-receptor tyrosine kinase array, EGFR signaling antibody array, and RNA sequencing (RNA-seq). Cell proliferation and ROS1 downstream signaling pathways were compared between HCC78 and HCC78CR1-3 cells.;RESULTS: ;The ROS1 G2032R mutation was identified in crizotinib-resistant tumors from one patient. Furthermore, HCC78CR1 and CR2 cells harbored a novel ROS1 L2155S mutation (73.3% and 76.2%, respectively). ROS1 G2032R and L2155S mutations conferred resistance to crizotinib in Ba/F3 cells. Evidence of epithelial-to-mesenchymal transition with downregulated E-cadherin and upregulated vimentin was observed in HCC78CR1-2 cells and in the other patient.

2.Population pharmacokinetics modeling and analysis of foretinib in adult patients with advanced solid tumors.

Singh RP;Patel B;Kallender H;Ottesen LH;Adams LM;Cox DS J Clin Pharmacol. 2015 Oct;55(10):1184-92. doi: 10.1002/jcph.546. Epub 2015 Jul 7.

Foretinib is a multikinase inhibitor that inhibits multiple receptor tyrosine kinases, including MET and VEGFR, with the potential for treatment of solid tumors. Hepatocellular carcinoma (HCC) pathogenesis is associated with overexpression of MET, and physiologic changes in the livers of HCC patients may decrease CYP3A isozyme-mediated metabolism of foretinib. A population pharmacokinetic model of foretinib was developed to explore the effect of tumor type, formulation, and other covariates. Data from 1 HCC study in Asia and 3 non-HCC studies in the United States with varying foretinib regimens and formulations were used for analysis. A 2-compartment model with a linear first-order absorption and elimination and lag time in absorption adequately described foretinib pharmacokinetics in 132 advanced non-HCC and HCC patients and identified an effect of formulations on bioavailability. The bisphosphate salt capsules and freebase tablets had a relative bioavailability 37% and 20% higher, respectively, than the solution formulation. HCC patients had ≈19.6% lower mean clearance (70.14 L/h), ≈16% lower mean volume of distribution (1725.6 L), and higher dose-normalized exposure compared with non-HCC patients.

3.Novel mechanism of lapatinib resistance in HER2-positive breast tumor cells: activation of AXL.

Liu L;Greger J;Shi H;Liu Y;Greshock J;Annan R;Halsey W;Sathe GM;Martin AM;Gilmer TM Cancer Res. 2009 Sep 1;69(17):6871-8. doi: 10.1158/0008-5472.CAN-08-4490. Epub 2009 Aug 11.

HER2-directed therapies, such as trastuzumab and lapatinib, are important treatments for breast cancer. However, some tumors do not respond or develop resistance to these agents. We isolated and characterized multiple lapatinib-resistant, HER2-positive, estrogen receptor (ER)-positive breast cancer clones derived from lapatinib-sensitive BT474 cells by chronic exposure to lapatinib. We show overexpression of AXL as a novel mechanism of acquired resistance to HER2-targeted agents in these models. GSK1363089 (foretinib), a multikinase inhibitor of AXL, MET, and vascular endothelial growth factor receptor currently in phase II clinical trials, restores lapatinib and trastuzumab sensitivity in these resistant cells that exhibit increased AXL expression. Furthermore, small interfering RNA to AXL, estrogen deprivation, or fulvestrant, an ER antagonist, decreases AXL expression and restores sensitivity to lapatinib in these cells. Taken together, these data provide scientific evidence to assess the expression of AXL in HER2-positive, ER-positive patients who have progressed on either lapatinib or trastuzumab and to test the combination of HER2-targeted agents and GSK1363089 in the clinic.

ConcentrationVolumeMass	1 mg	5 mg	10 mg
1 mM	1.5807 mL	7.9033 mL	15.8065 mL
5 mM	0.3161 mL	1.5807 mL	3.1613 mL
10 mM	0.1581 mL	0.7903 mL	1.5807 mL
50 mM	0.0316 mL	0.1581 mL	0.3161 mL

Foretinib is a multikinase ligand scaffold that may support MET/VEGFR-family degrader exploration. PROTAC design should focus on peripheral solvent-exposed vectors while preserving the heteroaryl kinase-binding region.

Structure: Foretinib is a multikinase ligand scaffold containing a quinoline/quinazoline-like heteroaryl core, a fluorinated aryl ether region, a substituted amide/urea-like side chain, and a basic heterocyclic amine. The structure combines rigid aromatic recognition elements with flexible polar substituents.

Reactivity: Foretinib-based PROTAC design should avoid modifying the heteroaryl kinase-binding core and instead explore solvent-facing side-chain or tertiary-amine-associated vectors. Alkyl, PEG, amide, urea, carbamate, or ether-containing linkers can be paired with CRBN, VHL, or IAP ligands if kinase binding is retained. Because foretinib is structurally complex, linker length and polarity should be optimized to balance target engagement, ternary-complex formation, and permeability.

We'd like to know that if foretinib can target FGFR2 in KATO-III before our research evaluation. Your help will be highly appreciated.

1 μM of foretinib inhibited phosphorylation of FGFR2 and downstream molecules, suggesting that foretinib targets FGFR2 in KATO-III.

11/12/2017

Can foretinib be used in genetic mouse model of endometrioid ovarian cancer?

Yeah, foretinib blocks proliferation, induces anoikis and impairs ovarian cancer cell adhesion, inhibits migration and invasion.

15/12/2018

Dear Sirs, Can you explain the activity of foretinib in vitro ?

Foretinib inhibits phosphorylation of MET and downstream signaling molecules in MKN-45 cells, while targets GFGR2 in KATO-III cells.

4/4/2020

Hello. Can foretinib induce apoptosis in vitro?

The foretinib inhibits Plk1 expression, reduces the survival and clonogenic capacity of IM-S and IM-R CML cells, and causes apoptosis through a caspase 2-mediated mechanism.

16/2/2022

How does foretinib target abnormal signaling of HGF?

Foretinib is developed to target abnormal signaling of HGF through Met and simultaneously target several receptors tyrosine kinase involved in tumor angiogenesis.

30/4/2022

Would you please tell me the mechanism of action of foretinib?

Foretinib works by binding to and selectively inhibiting the activity of specific RTKs, including the hepatocyte growth factor receptor (c-MET) and the vascular endothelial growth factor receptor 2 (VEGFR2).

2/6/2023

reduce tumor burden

Oral administration of Foretinib for one week reduced tumor burden, leading to tumor necrosis or even complete tumor regression in my animal models.

15/4/2016

mitigate nerve fiber loss

When our diabetic mice were treated with foretinib, a significantly larger volume of cutaneous nerve fibers was retained in the plantar skin compared to both vector-treated and untreated diabetic mice, while the proximal nerve fiber morphology was not affected.

17/12/2017

arrest KDR, Flt-1, and Flt-4

Foretinib can arrest KDR, Flt-1, and Flt-4 with IC50 values of 0.9 nM, 6.8 nM and 2.8 nM, respectively. Would recommend.

17/3/2020

block colony growth of B16F10

Foretinib works well for blocking colony growth of B16F10, A549 and HT29 cells with IC50 of 40 nM, 29 nM and 165 nM, respectively.

3/11/2020

inhibit HGF receptor family tyrosine kinases

In my experiment, Foretinib was used to inhibit HGF receptor family tyrosine kinases with IC50 values of 0.4 nM for Met and 3 nM for Ron. Worked well.

23/8/2022

enhance ploidy

Our experimental results found that foretinib-treated cells showed increased size, spindle assembly checkpoint abnormalities, and increased ploidy, all of which triggered mitotic catastrophe (MC).

13/10/2022

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It is commonly abbreviated as: C₁V₁ = C₂V₂