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Axitinib – A novel tyrosine kinase inhibitor

by Selleckchem | Mar 13 2012

Introduction

Axitinib (AG-013736) is a small molecule 2^nd generation inhibitor of tyrosine kinases (TKI). The unique aspect of this type of inhibitor is that they are orally administered yet remain a selective inhibitor of tyrosine kinases. Axitinib is a multi targeted inhibitor focusing on vascular endothelial growth factor receptors 1, 2 and 3 (VEGFR-1,2 or3), platelet derived growth factor receptor (PDGFR), and cKIT (CD117) [1]. VEGF is a functional part of the angiogenesis and vasculogenesis pathways and is frequently observed to be over expressed in various oncological conditions but not in normal tissue.[2-4] Targeting molecules to inhibit tyrosine kinases represents a new novel approach to chemotherapy and over 50 such molecules have been developed for clinical use, 10 of which have been approved for clincal use [5-7]. Axitinib is a pyrimidine core structure based on the first generation drug Imatinib., Imatinib was the first TKI to be approved for clinical use, it is used in the treatment of chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GIST) [8]. Axitinib is still under development by Pfizer inc, originally called AG013736 it is currently undergoing several phase 1 and phase 2 trial in renal carcinoma [9-13].

Axitinib – Preclinical investigations

Early translational investigations demonstrated that Axitinib inhibited the vascular development of xenogafts in mouse models. Epithelial cells were observed to lose fenestrations and after 7 days a 70 % decrease in vascular density was obtained. [14] It was established in phase 1 trials with patients with advanced solid tumours that Axitinib inhibited the VEGF signalling pathways. Renal cell carcinoma and pancreatic tumours have been reported as being highly dependent on VEGF over- expression, hence the Axitinib VEGFR inhibitor was investigated In vitro, initially focusing primarily pancreatic and renal cell carcinoma’s cell lines but also in a wide variety of other preclinical models [15-20] such as thyroid cancer [1;15;16] and breast cancer. [1;17-20].

Axitinib – Clinical trials

Phase 1 trials with Axitinib in renal cell carcinoma were conducted as single therapy and in combination with Sunitinib. Results demonstrated anti-tumor activity but was associated with less than expected success compared to the response seen in preclinical models [21-23]. These studies stressed the need to investigate the biology and pharmacology of these reagents to maximise their potential. In a separate instances Axitinib was used for patients with pancreatic cancer but a phase 2 Axitinib clinical trials in combination with gemcitabine was terminated due to no significant benefits being observed [24]. Axitinib is currently continuing being investigated in conjuction with mRCC in phase 2 and phase trials. Clinical investigation of Axitinib is on-going and despite some set backs in the phase ½ stages is still demonstrating promise in the treatment of renal cell carcinoma.

Axitinib – Availability and physical properties

Axitinib IC50 for VEGFR inhibition is 0.2 nmol/L. Axitinib solubility in ethanol and water is very poor but can be dissolved in DMSO up to33 mg/ml. Axitinib structure is based on a substituted pyrimidine core contains a centre of geometrical isomerism. Axitinib is commercially available as the trans form but in solution will rapidly convert to a cis / trans isomeric mixture unless protected from light [27]. Axitinib stability has been determined over 2 years when stored as a solid at -20^oC, stability in solution is subject to light degradation and should not be stored for longer than one year at -20°C. Research quality Buy Axitinib is available from several Axitinib suppliers at Axitinib prices ranging between $30 -60 for a 50 mg vial.

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