Foretinib (GSK1363089)

Description

Foretinib (GSK1363089) is an ATP-competitive inhibitor of HGFR and VEGFR, mostly for 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, PDGFRα/β and Tie-2, and little activity to FGFR1 and EGFR. Phase 2.

Description

Foretinib is a multikinase inhibitor that targets MET and VEGFR2 and also exhibits an inhibitory effect against KIT, Flt-3, PDGFRb, and Tie-2.

Uses

XL880 (GSK1363089, EXEL-2880) is an ATP-competitive inhibitor of MET and KDR with IC50 of 0.4 nM and 0.9 nM, respectively.

Uses

Foretinib (GSK1363089) is an ATP-competitive inhibitor of hepatocyte growth factor (HGF) and Vascular endothelial growth factor (VEGF) Receptor Tyrosine Kinases.

Definition

ChEBI: N1'-[3-fluoro-4-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinolinyl]oxy]phenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide is an aromatic ether.

Clinical Use

Foretinib has also shown to be effective against ROS1 mutations especially when acquired with crizotinib resistance. A clinical trial investigating the dosing and safety profile of combining foretinib and erlotinib was designed for advanced pretreated NSCLC patients.

Synthesis

Example 3: Preparation of N-[3-fluoro-4-({6-(methoxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N'-(4-fluorophenyl)cyclopropane-1,1 -dicarboxamide (Compound I, Form B). 3.1: Preparation of compound (I), crystalline form B. [0079] To a dry reactor (Reactor 1) was added 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (21.5 kg), THF (76 kg), and N,N-dimethylformamide (DMF, 0.09 kg), and stirred at 20 °C until completely dissolved. The reactor was cooled to about 15 °C and oxalyl chloride (12.7 kg) was slowly added over 38 min while controlling the internal temperature of the reactor below 20 °C. After the addition was complete, the transfer line was flushed with THF (3 kg). After 1 hour of reaction at about 20°C, oxalyl chloride (0.6 kg) and THF (2 kg) were added again to the reactor and the process was repeated once. Subsequently, smaller amounts of oxalyl chloride (0.13 kg) and THF (2 kg) were added a third time. To another dry reactor (reactor 2) was added water (60 L), K2CO3 (11.1 kg), 3-fluoro-4-[(6-methoxy-7-{[3-(4-morpholinyl)propyl]oxy}-4-quinolinyl)oxy]aniline (32.5 kg, see CAS Reg. No. 479690-10-3 and US2004/0242603 ) and THF (177 kg), and the temperature of the reactor contents was adjusted to about 15 °C. The contents of Reactor 1 were slowly added to Reactor 2 while keeping the temperature of Reactor 2 below 20°C. Rinse Reactor 1 with THF (5 kg) and transfer the rinse solution to Reactor 2. The temperature of the contents of Reactor 2 was adjusted to about 20 °C and the reaction was carried out for about 3 hours. Subsequently, 0.8M K2CO3 aqueous solution (171 kg) and isopropyl acetate (119 kg) were added, stirred for 10 minutes, left to stratify, and the lower aqueous phase was discarded. Repeatedly added 0.8M K2CO3 aqueous solution (171kg), mixed and left to stratify, again discarded the aqueous phase. Water (137 kg) was added, mixed and allowed to partition, and the aqueous phase was discarded. Steam-activated powdered activated carbon (Darco G-60, Norit Americas, Inc., 3.4 kg) and isopropyl acetate (3 kg) were added, stirred for about 2.5 hours, and then filtered through a filter containing diatomaceous earth into another reactor (Reactor 3). The reactor 2 was rinsed twice with isopropyl acetate (33 kg each time) and the rinsate was combined with the material in reactor 3 through the above mentioned filter. The material in Reactor 3 was concentrated to about 104 L under vacuum, keeping the temperature below 50°C. Isopropanol (161 kg) was added and again concentrated under vacuum to about 104 L, keeping the temperature below 50°C. Repeatedly added isopropanol (161 kg) and concentrated to about 100 L. Heated the material in Reactor 3 to about 75°C, held for 80 minutes, and then cooled to about 55°C. Heptane (1 kg) containing about 1% isopropanol was added and held at about 55°C for 70 minutes until crystallization was observed. Subsequently, heptane (46 kg) containing about 1% isopropanol was added and the reactor contents were kept at about 55°C for 75 minutes. The reactor contents were cooled to about 20°C over a period of about 5 hours and held at that temperature for about 12 hours. Further cooling to about 5°C and holding for 1 hour. The material in reactor 3 was transferred to a filter drier and rinsed with a mixture of isopropanol (18 kg) and heptane (8 kg). Drying at about 50°C for about 56 hours gave 42.8 kg (89% yield) of compound (I) crystalline form B as an off-white powder.

in vitro

In vitro, foretinib blocks activation of MET and VEGFR2-induced signaling pathways. In vivo experiments show a dose-dependent decrease in tumor burden in a lung metastasis experimental model.

target

Met

References

[1] qian f1, engst s, yamaguchi k, yu p, won ka, mock l, lou t, tan j, li c, tam d, lougheed j, yakes fm, bentzien f, xu w, zaks t, wooster r,greshock j, joly ah. inhibition of tumor cell growth, invasion, and metastasis by exel-2880 (xl880, gsk1363089), a novel inhibitor of hgf and vegf receptor tyrosine kinases. cancer res. 2009 oct 15;69(20):8009-16. doi: 10.1158/0008-5472.can-08-4889.