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LINIFANIB-A FIRST LINE INHIBITOR AGAINST CANCER

RECEPTOR TYROSINE KINASES AND CANCER
Receptor tyrosine kinases (RTKs) are transmembrane receptors that start signaling cascade inside the cell after getting stimulated by different types of respective ligands.  The stimulation may arise from the immediate or far away surroundings of the cell. Actually they respond to the needs of their extracellular environment by stimulating or inhibiting different types of cellular activities of regulation of cell cycle e.g., expressing or inhibiting a gene.  After getting stimulated they phosphorylate themselves, dimerize and initiate a signaling cascade in multiple dimensions showing amplified effect of a single ligand. As these receptors have multiple types of effects therefore any change in their structure might lead to a gross change in the activities and behavior of the cell. As they are cell cycle regulatory proteins there over or under expression may lead to different types of diseases like cancer.


LINIFANIB – RECEPTOR TYROSINE KINASE INHIBITOR
As receptor tyrosine kinases are the entry site for cell cycle regulatory activities, inhibiting this first level of activity flaw may be quite beneficial in treatment of diseases involving RTK defect. Any inhibitor against these RTKs is very beneficial and research in this area is welcomed. Linifanib is one of such inhibitors that have shown a promising activity against multiple types of RTKs. The anti-tumor activity of this inhibitor was discovered after its tumor regression activity in human fibrosarcoma cells HT1080 xenografts and murine models of uterine edema which were induced by estradiol [1]. The Linifanib was synthesized by drug designing by chemical modifications and testing [2].


THE PROPERTIES OF LINIFANIB AND ITS EFFICACY IN CELL SYSTEM
Linifanib contains aminoindazole ring in it. This molecule is small and is specific against different types of RTKs. The endothelial cells from humans used to measure the activity showed IC50 of 4nM, 2nM and 0.2nM for inhibition of CSF-1R (colony stimulating factor receptor-1), KDR phosphorlyation and PDGFR-respectively. It is sold under the name of Linifanib-ABT-869 and researchers or scientists can buy Linifanib in the form of a 10 mg vial in $250. Linifanib is soluble in DMSO and can remain stable for upto 2 years at -20 degrees.
Linifanib FLT3 inhibitor has shown induction of apoptosis in in vivo conditions in hematopoietic cells as well as in in-vitro conditions. Similarly reduction in phosphorylation has been seen in Akt and GSK-3 [3]. In acute myloid leukemia (AML) cells having FLT3 in wild type, Linifanib showed decrease in tumor growth and its regression [4]. Linifanib has shown an effect on VEGFR phosphorlyation by decreasing the vascularity in preclinical models of tumor in fibrosarcoma cells HT1080 and colon carcinoma (CC) cells SW620 [5]. When Linifanib is given in chemotherapy, it has been seen to downregulate the MAPK pathway and the genes having a role in cell cycle [6].


EFFICACY OF LINIFANIB IN CLINICAL AND PRECLINICAL TRIALS
Linifanib VEGFR-PDGFR inhibitor
is very potent against different types of tumors. It has been shown in murine models [7]. Linifanib treatment has shown a stabilization in 50 % patients with refractory solid tumors in clinical trial phase I and when assessed for biomarkers [8]. The developing company of this drug has launched its phase II and III trials for determining the safety, tolerance and efficacy in HCC (hepatocellular carcinoma) patients in advanced stage and for comparing the efficacy of this drug with that of Sofranib respectively. Similarly a comparative study has been done on patients with advanced colorectal cancer in clinical trial phase II by Abbott pharmaceuticals to check the synergism in activity of Linifanib combined with mFOLFOX6 (Folinic Acid, 5-Fluorouracil and Oxaliplatin) and compared it with the combination of  Bevacizumab with mFOLFOX6.


REFERENCES:          
1. Dai, Y.e.a., Discovery of N-(4-(3-Amino-1H-indazol-4-yl)phenyl)-N‘-(2-fluoro-5-methylphenyl)urea (ABT-869), a 3-Aminoindazole-Based Orally Active Multitargeted Receptor Tyrosine Kinase Inhibitor. J. Med. Chem., 2007.
2. Kruger, A.W.e.a., The Discovery and Development of a Safe, Practical Synthesis of ABT-869. Org. Process Res. Dev., 2009.
3. Davies, J.E.e.a., 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.
4. Zhou, J.e.a., In vivo activity of ABT-869, a multi-target kinase inhibitor, against acute myeloid leukemia with wild-type FLT3 receptor. Leukemia Research, 2008.
5. Jiang, F.e.a., ABT-869, a Multitargeted Receptor Tyrosine Kinase Inhibitor, Reduces Tumor Microvascularity and Improves Vascular Wall Integrity in Preclinical Tumor Models. JPET, 2011.
6. Zhou, J.e.a., Synergistic antileukemic effects between ABT-869 and chemotherapy involve downregulation of cell cycle-regulated genes and c-Mos-mediated MAPK pathway: Synergism of ABT-869 and chemotherapy. Leukemia, 2008.
7. Albert, D.H.e.a., Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor. Molecular Cancer Therapeutics, 2006.
8. Wong, C.e.a., Phase I and Biomarker Study of ABT-869, a Multiple Receptor Tyrosine Kinase Inhibitor, in Patients With Refractory Solid Malignancies. Journal of Clinical Oncology, 2009.

 

Related Products

Cat.No. Product Name Information
S1003 Linifanib (ABT-869) Linifanib (ABT-869, AL39324, RG3635) is a novel, potent ATP-competitive VEGFR/PDGFR inhibitor for KDR, CSF-1R, Flt-1/3 and PDGFRβ with IC50 of 4 nM, 3 nM, 3 nM/4 nM and 66 nM respectively, mostly effective in mutant kinase-dependent cancer cells (i.e. FLT3). Linifanib (ABT-869) induces autophagy and apoptosis. Phase 3.

Related Targets

FLT3