Linifanib (ABT-869, AL39324, RG3635) is a novel and potent ATP-competitive VEGFR/PDGFR inhibitor against KDR, CSF-1R, Flt-1/3, and PDGFRβ with IC50 of 4 nM, 3 nM, and 4 nM, respectively. 3 nM/4 nM and 66 nM, were most effective against mutant kinase-dependent cancer cells (i.e., FLT3). Linifanib (ABT-869) induces autophagy and apoptosis. Phase 3.

 

Brand: BCM

 

Target: Apoptosis; c-Fms; VEGFR; FLT; CSF-1R; PDGFR; c-Kit; Autophagy

 

Signaling Pathways: Angiogenesis; Apoptosis; Autophagy; Tyrosine Kinase/Adaptors

 

In Vitro: In lung tissue,Linifanib (0.3 mg/kg) completely inhibited vascular endothelial growth factor receptor phosphorylation. On the cornea, twice-daily Linifanib (7.5/15 mg/kg) significantly inhibited recombinant basic fibroblast growth factor-and vascular endothelial growth factor-induced angiogenesis. Linifanib (12.5 mg/kg twice daily) reduced microvessel density in MDA-231 xenografts. Linifanib also inhibited the edema response (ED50:0.5 mg/kg). Linifanib inhibited tumor growth in transplanted tumor models including HT1080, H526, MX-1 and DLD-1 (ED75:4.5-12 mg/kg). The Cmax and AUC24 hours of Linifanib were 0.4 μg/mL and 2.7 μg·hour/mL, respectively, in the HT1080 fibrosarcoma model.

 

In Vivo: ABT-869 inhibited the proliferation of human umbilical artery endothelial cells stimulated by vascular endothelial growth factor (VEGF) (IC50:0.2 nM). In kinase assays,Linifanib inhibited Kit (IC50:14 nM), PDGFRβ (IC50:66 nM), and Flt4 (IC50:190 nM). Linifanib also inhibited ligand-induced phosphorylation of KDR (IC50:2 nM), PDGFR-β (IC50:2 nM), KIT (IC50:31 nM), and CSF-1R (IC50:10 nM) at the cellular level, with serum proteins influencing this potency. Linifanib (10 nM) reduced Akt phosphorylation at Ser473 and GSK3β phosphorylation at Ser9 in Ba/F3 FLT3 ITD cells. However,ABT-869 barely affected tumor cells that were not induced by vascular endothelial growth factor or platelet-derived factor, with the exception of MV4-11 leukemia cells (which have a constitutively active form of Flt3, IC50:4 nM). Linifanib binds to the ATP-binding site of CSF-1R (Ki: 3 nM).

 

Melting Point: 180-183°C (dec.)

 

Boiling Point: 542.2±50.0 °C(Predicted)

 

pKa: 13.30±0.70(Predicted)

 

Solubility: Soluble in DMSO. Insoluble in Water; Insoluble in Ethanol.

 

GHS: GHS08, GHS09

 

Isomeric SMILES: CC1=CC(=C(C=C1)F)NC(=O)NC2=CC=C(C=C2)C3=C4C(=CC=C3)NN=C4N  

 

InChIKey: MPVGZUGXCQEXTM-UHFFFAOYSA-N  

 

InChI: InChI=1S/C21H18FN5O/c1-12-5-10-16(22)18(11-12)25-21(28)24-14-8-6-13(7-9-14)15-3-2-4-17-19(15)20(23)27-26-17/h2-11H,1H3,(H3,23,26,27)(H2,24,25,28)

 

Attribute
[Chem Name]	1-[4-(3-amino-1H-indazol-4-yl)phenyl]-3-(2-fluoro-5-methylphenyl)urea
[Synonym]	Linifanib; ABT-869; AL39324; RG3635
[CAS No.]	796967-16-3
[MDL No.]	MFCD11840918
[Formula]	C21H18FN5O
[Molecular]	375.4
[Form]	Brown to beige powder
[Storage]	Keep in dark place. Inert atmosphere, 2-8°C

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