XL880 ; A BROAD SPECTRUM KINASE INHIBITOR

by Selleckchem | Mar 20 2012

XL880 AND THE INFERENCE OF INHIBITION OF VEGF-R/MET/KDRIN TUMORS

Many types of cancers exhibit the over expression of Met receptor tyrosine kinase or MTK, kinase domain receptors or KDRs contributing to tumor progression and hepatocyte growth factor or HGF (ligand of MTK). These KDRs are in fact is similar to interacting protein of MTKs, which is vascular endothelial growth factor or VEGF receptors. So the use of an inhibitor molecule which can inhibit these receptors can be a very valuable and attractive approach to treat cancers. XL880 MET inhibitor exhibits the same role. Another descriptive name for The XL880 VEGFR inhibitor is a EXEL-2880 (due to its discovery by the company named Exelixis) or Foretinib or GSK089 or GSK1363089 (now GlaxoSmithKline is also producing XL880 KDR inhibitor). XL880 structure reveals that it is a derivative of dicarboxamide. XL880 prices are not very low. Anyone can buy XL880 vial of 10 mg by paying $250 to XL880 suppliers. In DMSO XL880 solubility can be achieved while XL880 stability is around 2 years if stored at or below -20^oC. To achieve an effective KDR and MET inhibition, XL880 IC50 is 0.8 nM and 0.4 nM respectively.

PRECLINICAL ANALYSIS OF XL880:

In case of tumor cell lines in human, amplification of combination of HER1 and HER2⁺with MET⁺is responsible of making the cell lines more susceptible for the XL880 in combination with Lapatinib or Erlotinib while the amplification of the combination of HER1^– or HER2^–with MET⁺makes the cell lines sensitive to XL880 alone [1]. Another example is of gastric cells carcinoma in which the amplification of MET⁺ but FGFR2^–makes these cell lines sensitive to XL880 treatment [2]. According to another report the over expression of AXL also contributes to sensitivity of XL880 in cancer cells which are resistant to chemotherapy [3]. Treatment with XL880 in murine model of genetic adenocarcinoma, was found to be result in the inhibition of activation of c-Met and prevention of the growth of these cancers from primary stages to invasive stages along with the decrease in metastatic properties and tumor size [4].

XL880: CLINICAL SUCCESS

XL880 is the first ever inhibitor used in the clinics. According to XL880 clinical trials , it was found that it is very well tolerate able in patients. It causes the regression of tumors in both hypoxic and normoxic conditions by inhibiting the anchorage-independent increase in tumor cells [5]. Clinical trials phase I of XL880 has shown that it is well tolerated at clinically relevant dosage [6] which was about 240 mg in phase I and was also used in phase II trials of XL880 [7]. It also promises partial responses and those were gained in patients having solid tumors in phase I analysis [8]. It was observed that 65% of patients of head and neck tumors (NCT00725764) gain stable disease after 1 year of the treatment with XL880, when they are undergone clinical trials of phase II [9-10]. Tolerance, response and safety profile of XL880 was analyzed in patients of liver carcinoma NCT00920192) also known as advanced hepatocellular carcinoma and papillary renal carcinoma (NCT00726323) in different clinical trials by using GlaxoSmithKline as a phase II study. Some studies of NCIC as clinical trials of phase II is implementing the XL880 against breast cancer (NCT01147484) "triple negative". According to another phase I NCIC study, the clinically relevant and safe dose of Lapatinib and XL880 co-treatment in patients of breast carcinoma was recommended for making the proper assessment of the efficiency of thecombination in terms of endurance as compared to Lapatinib used alone (NCT01138384).

REFERENCES:

1. Liu, L.e.a., Synergistic Effects of Foretinib with HER-Targeted Agents in MET and HER1- or HER2-Coactivated Tumor Cells. Mol Cancer Ther, 2011.

2. Kataoka, Y.e.a., Foretinib (GSK1363089), a multi-kinase inhibitor of MET and VEGFRs, inhibits growth of gastric cancer cell lines by blocking inter-receptor tyrosine kinase networks. Investigational New Drugs, 2011.

3. Liu, L.e.a., Novel Mechanism of Lapatinib Resistance in HER2-Positive Breast Tumor Cells: Activation of AXL. Cancer Res, 2009.

4. Zillhardt, M.e.a., Foretinib (GSK1363089), an Orally Available Multikinase Inhibitor of c-Met and VEGFR-2, Blocks Proliferation, Induces Anoikis, and Impairs Ovarian Cancer Metastasis. Clin Cancer Res, 2011.

5. Qian, F.e.a., Inhibition of Tumor Cell Growth, Invasion, and Metastasis by EXEL-2880 (XL880, GSK1363089), a Novel Inhibitor of HGF and VEGF Receptor Tyrosine Kinases.Cancer Res, 2009.

6. Hedgethorne, K.a.H., P.H., FORETINIB. DRUGS OF THE FUTURE, 2011.

7. Eder, J.P.e.a., A Phase I Dose-Escalation Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Early Antitumor Activity of Foretinib. Clin Cancer Res, 2010.

8. Ross, R.W.e.a., A phase II study of the c-Met RTK inhibitor XL880 in patients (pts) with papillary renal-cell carcinoma (PRC). Journal of Clinical Oncology, 2007.

9. Elferink, L.A.a.R., V.A., Receptor-Tyrosine-Kinase-Targeted Therapies for Head and Neck Cancer. Journal of Signal Transduction, 2011.

10. Comoglio, P.M.e.a., Drug development of MET inhibitors: targeting oncogene addiction and expedience. Nature Reviews Drug Discovery, 2008.