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Axitinib – A novel tyrosine kinase inhibitor

Introduction

Axitinib (AG-013736) is a small molecule 2nd 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 -20oC, 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.

References

 

   1.   Choueiri TK. Axitinib, a novel anti-angiogenic drug with promising activity in various solid tumors. Curr Opin Investig Drugs 2008; 9(6):658-671.

   2.   Botelho F, Pina F et al. VEGF and prostatic cancer: a systematic review. Eur J Cancer Prev 2010; 19(5):385-392.

   3.   Chodorowska G, Chodorowski J et al. Vascular endothelial growth factor (VEGF) in physiological and pathological conditions. Ann Univ Mariae Curie Sklodowska Med 2004; 59(2):8-14.

   4.   Mukhopadhyay D, Datta K. Multiple regulatory pathways of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) expression in tumors. Semin Cancer Biol 2004; 14(2):123-130.

   5.   Quintas-Cardama A, Kantarjian H et al. Third-generation tyrosine kinase inhibitors and beyond. Semin Hematol 2010; 47(4):371-380.

   6.   Saijo N, Kenmotsu H. Recent development of molecular-targeted drugs in lung cancer. Intern Med 2010; 49(18):1923-1934.

   7.   Ye L, Santarpia L et al. The evolving field of tyrosine kinase inhibitors in the treatment of endocrine tumors. Endocr Rev 2010; 31(4):578-599.

   8.   Agrawal M, Garg RJ et al. Tyrosine kinase inhibitors: the first decade. Curr Hematol Malig Rep 2010; 5(2):70-80.

   9.   Steffens S, Grunwald V et al. Does obesity influence the prognosis of metastatic renal cell carcinoma in patients treated with vascular endothelial growth factor-targeted therapy? Oncologist 2011; 16(11):1565-1571.

10.   Fruehauf J, Lutzky J et al. Multicenter, Phase II Study of Axitinib, a Selective Second-Generation Inhibitor of Vascular Endothelial Growth Factor Receptors 1, 2, and 3, in Patients with Metastatic Melanoma. Clin Cancer Res 2011; 17(23):7462-7469.

11.   Coppin C, Kollmannsberger C et al. Targeted therapy for advanced renal cell cancer (RCC): a Cochrane systematic review of published randomised trials. BJU Int 2011; 108(10):1556-1563.

12.   Spano JP, Moore MJ et al. Phase I study of axitinib (AG-013736) in combination with gemcitabine in patients with advanced pancreatic cancer. Invest New Drugs 2011.

13.   Michael M, Vlahovic G et al. Phase Ib study of CP-868,596, a PDGFR inhibitor, combined with docetaxel with or without axitinib, a VEGFR inhibitor. Br J Cancer 2010; 103(10):1554-1561.

14.   Inai T, Mancuso M et al. Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts. Am J Pathol 2004; 165(1):35-52.

15.   Cohen EE, Rosen LS et al. Axitinib is an active treatment for all histologic subtypes of advanced thyroid cancer: results from a phase II study. J Clin Oncol 2008; 26(29):4708-4713.

16.   Sherman SI. Early clinical studies of novel therapies for thyroid cancers. Endocrinol Metab Clin North Am 2008; 37(2):511-24, xi.

17.   Ito Y, Kobayashi K. [Chemotherapy for breast cancer refractory to anthracycline, taxane or trastuzumab]. Gan To Kagaku Ryoho 2009; 36(5):726-729.

18.   Li KL, Wilmes LJ et al. Heterogeneity in the angiogenic response of a BT474 human breast cancer to a novel vascular endothelial growth factor-receptor tyrosine kinase inhibitor: assessment by voxel analysis of dynamic contrast-enhanced MRI. J Magn Reson Imaging 2005; 22(4):511-519.

19.   Mundhenke C, Strauss A et al. Significance of Tyrosine Kinase Inhibitors in the Treatment of Metastatic Breast Cancer. Breast Care (Basel) 2009; 4(6):373-378.

20.   Poller B, Iusuf D et al. Differential impact of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) on axitinib brain accumulation and oral plasma pharmacokinetics. Drug Metab Dispos 2011; 39(5):729-735.

21.   George DJ. Phase 2 studies of sunitinib and AG013736 in patients with cytokine-refractory renal cell carcinoma. Clin Cancer Res 2007; 13(2 Pt 2):753s-757s.

22.   Rini BI, Jaeger E et al. Clinical response to therapy targeted at vascular endothelial growth factor in metastatic renal cell carcinoma: impact of patient characteristics and Von Hippel-Lindau gene status. BJU Int 2006; 98(4):756-762.

23.   Rugo HS, Herbst RS et al. Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: pharmacokinetic and clinical results. J Clin Oncol 2005; 23(24):5474-5483.

24.   Spano JP, Chodkiewicz C et al. Efficacy of gemcitabine plus axitinib compared with gemcitabine alone in patients with advanced pancreatic cancer: an open-label randomised phase II study. Lancet 2008; 371(9630):2101-2108.

25.   Albiges L, Salem M et al. Vascular endothelial growth factor-targeted therapies in advanced renal cell carcinoma. Hematol Oncol Clin North Am 2011; 25(4):813-833.

26.   Escudier B, Gore M. Axitinib for the management of metastatic renal cell carcinoma. Drugs R D 2011; 11(2):113-126.

27.   Kania RS, . Structure-based design and characterisation of Axitinib. In: Li R, editor. Kinase inhibitor drugs. John Wiley & Sons; 2009.

Related Products

Cat.No. Product Name Information
S1005 Axitinib (AG 013736) Axitinib (AG 013736) is a multi-target inhibitor of VEGFR1, VEGFR2, VEGFR3, PDGFRβ and c-Kit with IC50 of 0.1 nM, 0.2 nM, 0.1-0.3 nM, 1.6 nM and 1.7 nM in Porcine aorta endothelial cells, respectively.

Related Targets

VEGFR