A2949-5mg | Linifanib (ABT-869) [796967-16-3] Clinisciences

Background

Linifanib (ABT-869) is an effective ATP-competitive tyrosine kinase inhibitor against the platelet-derived growth factor (PDGF) receptor and the vascular endothelial growth factor receptor (VEGFR) families, including constitutively active FMS-like receptor tyrosine kinase 3 (FLT3) [1][2]. It is of IC50 values of 0.55 nmol/L and 6 μmol/L to the cell growth in Ba/F3 FLT3 ITD mutant cells and in Ba/F3 FLT3 WT cells, respectively [1].

FLT3 is important in controlling the proliferation and differentiation of hematopoietic cells. Patients with acute myeloid leukemia (AML) showed activating mutations in FLT3. These mutations caused abnormal cell proliferation [1].

Linifanib at a concentration of 10 nmol/L induced apoptosis in internal tandem duplication (ITD) mutant cells, but showed no effect in WT cells. Treatment with linifanib did not differentiate WT cells from FLT3 mutant cells with mutation at D835V, in inhibiting proliferation or reducing cell viability. In Ba/F3 FLT3 ITD cell lines, linifanib at a concentration of 10 nmol/L, effectively inhibited the phosphorylation of FLT3. 10 nmol/L linifanib reduced the phosphorylation of Akt at Ser473 [1].

Daily orally treatment with linifanib by gavage in NOD/SCID mice with ITD mutant cell decreased the leukemia progression rate compared with the control. On day 7, ITD mutant cells showed rapid progression in control mice, whereas linifanib-treated mice showed no detectable disease. In addition, daily linifanib-treated mice with ITD mutant cells showed significantly longer (P < 0.01) survival duration than control mice with ITD mutant cells only [1].

References:
[1]. Jenny E. Hernandez-Davies, Joan P. Zape, Elliot M. Landaw, et al. The Multitargeted Receptor Tyrosine Kinase Inhibitor Linifanib (ABT-869) Induces Apoptosis through an Akt and Glycogen Synthase Kinase 3β–Dependent Pathway. Mol. Cancer Ther., 2011, 10(6):949-59.
[2]. Joyce E. Ohm, Michael R. Shurin, Clemens Esche, et al. Effect of Vascular Endothelial Growth Factor and FLT3 Ligand on Dendritic Cell Generation In Vivo. Journal of Immunology, 1999, 163:3260-3268.

Chemical Properties

Storage	Store at -20°C
M.Wt	375.41
Cas No.	796967-16-3
Formula	C₂₁H₁₈FN₅O
Solubility	insoluble in H2O; insoluble in EtOH; ≥18.75 mg/mL in DMSO
Chemical Name	1-[4-(3-amino-1H-indazol-4-yl)phenyl]-3-(2-fluoro-5-methylphenyl)urea
SDF	Download SDF
Canonical SMILES	CC1=CC(=C(C=C1)F)NC(=O)NC2=CC=C(C=C2)C3=C4C(=CC=C3)NN=C4N
Shipping Condition	Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice.
General tips	We do not recommend long-term storage for the solution, please use it up soon.

Protocol

Cell experiment [1]:
Cell lines	Ba/F3 FLT3 ITD mutant and WT cells
Preparation method	The solubility of this compound in DMSO is > 10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below - 20 °C for several months.
Reacting condition	0.1 nM ~ 10 μM; 24 hrs
Applications	Linifanib was more effective at inhibiting cell growth in ITD mutant cells with the IC50 value of 0.55 nM. In addition, treatment with 10 nM of Linifanib induced apoptosis in ITD mutant cells, but showed no observable effect on WT cells.
Animal experiment [1]:
Animal models	NOD/SCID mice with ITD mutant cells
Dosage form	0.2 mL/20 g; p.o.; q.d.
Applications	In NOD/SCID mice with ITD mutant cells, Linifanib decreased leukemia progression. On day 7, untreated mice exhibited rapid progression of ITD mutant cells, whilst mice treated with Linifanib showed no detectable disease. In addition, Linifanib significantly prolonged survival duration of Ba/F3 FLT3 ITD-injected mice.
Other notes	Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
References: [1]. Jenny E. Hernandez-Davies, Joan P. Zape, Elliot M. Landaw, et al. The Multitargeted Receptor Tyrosine Kinase Inhibitor Linifanib (ABT-869) Induces Apoptosis through an Akt and Glycogen Synthase Kinase 3β–Dependent Pathway. Mol. Cancer Ther., 2011, 10(6):949-59.

Biological Activity

Description	Linifanib is a multitargeted inhibitor of receptor tyrosine kinase with IC50 value of 3 nM, 3 nM, 4 nM, 4 nM and 14 nM for VEGFR1/FLT1, CSF-1R, VEGFR2/KDR, FLT3 and KIT, respectively.
Targets	VEGFR1/FLT1	CSF-1R	VEGFR2/KDR	FLT3	KIT
IC50	3 nM	3 nM	4 nM	4 nM	14 nM