LINIFANIB: INHIBITOR FOR RECEPTOR ENZYMES

by Selleckchem | Mar 28 2012

LINIFANIB: A MULTIPLE KINASE INHIBITIOR:
Receptor tyrosine kinases are the enzymes which are responsible of receiving signals from neighboring cells and extracellular environment so they are mostly the initiating point for the different signaling pathways and hence known as sentry of cells. Due to their importance in different signaling cascades, even very small changes in the activity or structure of RTKs can get magnify in form of differential signaling and leads to an entirely different outcome. In various diseased conditions, especially cancers, different receptor tyrosine kinases are either dysregulated or over expressed and finally lead to target the very first signaling level, which is an attractive approach in anti-tumor therapeutics. Due to their broad spectrum of action, it’s testing and development is very much welcome. Linifanib is a small inhibitor molecule which targets more than one Receptor tyrosine kinase enzymes. The potential anti-cancer property of Linifanib PDGFR inhibitor was discovered when its tumor regression in xenografts of human fibrosarcoma cells HT1080 and in estradiol-induced uterine edema’s model of murine [1]. Synthesis of Linifanib took place as a side product of chemical modification in certain drugs [2].

PROPERTIES OF LINIFANIB AND ITS EFFICACY IN CELLULAR SYSTEMS:
Structure of Linifanib showed the existence of a ring of aminoindazole. This novel and small inhibitor molecule has a broad spectrum of action against many receptor tyrosine kinases. Linifanib IC50 for effective PDGFR-, inhibition of KDR phosphorylation and CSF-1R in endothelial cells of human is 0.2 nM, 2 nM and 4 nM respectively. One can purchase Linifanib from Linifanib suppliers by paying the price of a 10 mg packing around almost $250 under trade name ABT-869. Linifanib is efficiently soluble in DMSO and is stable for almost 2 years if stored at -20oC.

LINIFANIB: PRECLINICAL AND CLINICAL EFFICIENCY
Linifanib RTK inhibitor causes the stimulation of apoptotic cell death in vivo and in vitro hematopoetic cellular models by suppressing the signaling of FLT3 and reducing the phosphorylation process of GSK-3 β (glycogen synthase kinase-3 β) and Akt [3]. Linifanib also found to cause a great tumor regression in cells of acute myeloid leukemia with FLT3 wild type [4]. In preclinical cancer models of cells of colon carcinoma SW620 and fibrosarcoma HT1080, Linifanib caused a significant change in VEGFR phosphorylation which was the decrease in their vascularity [5]. This inhibitor was also found to show a synergistic role on down regulation of Map kinase pathway and genes for cell cycle when induced in combination with chemotherapy [6].

Linifanib usage in murine models in vivo has shown remarkable potential of Linifanib VEGFR-PDGFR inhibitor [7]. Upon treatment of patients having refractory solid malignant tumors with Linifanib, a stabilized disease was reported in almost 50% of them by studies of biomarker assessment and phase I clinical trials [8]. Abbott pharmaceuticals , the manufacturers of Linifanib has launched a clinical trial of phase II to analyze its efficaciousness, tolerance in HCC patients (NCT00517920) and safety and also comparison of efficiencies of Sorafanib and Linifanib in another study of phase III (NCT01009593). Another similar phase II clinical trial of Linifanib from Abbott checks the synergistic effect of mFOLFOX6 (Folinic Acid, 5-Fluorouracil and Oxaliplatin) and Linifanib as compared to combination of Bevacizumab-mFOLFOX6 in case of patients of advanced colorectal carcinoma (NCT00707889).

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.