ABT-869 – THE MULTI KINASE INHIBITOR

by Selleckchem | Mar 13 2012

ABT-869 – Tyrosine Kinase Inhibition:

Tyrosine kinase is a family of enzymes that utilize phosphorylation of proteins to determine activity of many cellular functions. Tyrosine kinases are a sub family of the protein kinases which phosphorylate serine and threonine for cellular control. Mutation at the genetic level has been observed in this family of enzymes, which leads to the enzyme becoming unregulated. This over expression is observed in many cancer cell lines and represents a target for chemotherapy treatment. Tyrosine kinase inhibitors are novel small molecules which have come to the forefront of cancer research in recent times. Based on the designed molecule Imatinib, TKI’s have been developed to inhibit a wide range of tyrosine kinase receptor either as a single targeted or as a multiple targeted drug. ABT-869 PDGFR inhibitor, marketed under the trade name Linifanib, is a multi-targeted inhibitor against PDGFR-β, KDR, CSF-1R, FLT1, FLT4, KIT, FLT3 and Tie2 [1].

Pre-clinical aspects of ABT-869:

ABT-869 RTK inhibitor has been tested in human xenograft tumor models of HT1080 (fibrosarcoma) demonstrating significant tumor growth inhibition [1;2], this stimulated extensive work in breast, colon and small cell ling carcinoma xenograft models. ABT-869 demonstrated >50% inhibitory effects in all models systems tested [3] with ABT-869 IC50 of 0.2 nM (PDGFR-ß) , 2 nM (KDR) and 4 nM (CSF-1R). The mechanism of action for ABT-869 was investigated and demonstrated that suppression of FLT3 signaling coupled with a decrease in phosphorylation of both AKT and GSK-3β induced apoptosis [4]. ABT-869’s anti-tumor effect has been linked to the inhibition FLT3 in over expressing models [5]. Models that do not over express VEGF or PDGF do not demonstrate significant activity.

Interestingly ABT-869 demonstrated activity in the Ewing Sarcoma (EWS) family of tumours which are known to express PDGFR and c-KIT. EWS is one of the most common adolescent tumours but clinical prognosis is poor (<30%) after 5 years. ABT-869 represents a new approach for this disease enabling an easier form of treatment since ABT-869 is orally administered. [6] In an investigation of combinations of ABT-869 with traditional chemotherapy (cytaribine and doxorubicin) synergistic results have been observed. Down regulation of the cell cycle check points and mitogen protein kinases (CCND! And c-MOS respectively) was demonstrate as being the driving mechanism for the sysnergy. Such significant results have lead to ABT-869 being taken into phase 1 and phase 2 clinical trials.

Clinical investigations of ABT-869 VEGFR inhibitor

Phase 1 studies have been conducted in subjects with refractory solid tumor cancers to determine the maximum tolerated dose (MTD). 0.3 mg/kg/day was determined to be the MTD with 48% showing stable disease after 15 days, only 9% demonstrated tumor reduction over the course of treatment.[7] Two phase 2 studies are ongoing with advanced hepatocellular carcinomas (HCC) and advance colorectal cancer patients (in combination with FOLFOX6). The later was compared to the same combination but with Bevacizumab. Two reported phase 2 trials with renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC) have been concluded and reported. In NSCLC ABT-869 was found to be active even as a 2^nd or 3^rd lines of chemotherapy and survival benefits were observed [8]. For RCC clear clinical benefits were observed in patients that failed Sunitinib treatment indicated further investigation with ABT-869 is warranted [9].

ABT- Availability and known properties

ABT-869 structure is based on an amino substituted indazole and ABT-869 solubility is similar to all tyrosine kinase inhibitors, with poor solubility in water and ethanol but soluble in DMSO up to 20 mg/ml. You can Buy ABT-869 in research quality from various ABT-869 suppliers with ABT-869 price ranging from $200 to 250 for a 10 mg vial. ABT-869 stability in solution is not reported but the solid product is stable upto 2 years if stored at -20°C.

References

1. Albert DH, Tapang P et al. Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor. Mol Cancer Ther 2006; 5(4):995-1006.

2. Guo J, Marcotte PA et al. Inhibition of phosphorylation of the colony-stimulating factor-1 receptor (c-Fms) tyrosine kinase in transfected cells by ABT-869 and other tyrosine kinase inhibitors. Mol Cancer Ther 2006; 5(4):1007-1013.

3. Jiang F, Albert DH et al. ABT-869, a multitargeted receptor tyrosine kinase inhibitor, reduces tumor microvascularity and improves vascular wall integrity in preclinical tumor models. J Pharmacol Exp Ther 2011; 338(1):134-142.

4. Shankar DB, Li J et al. ABT-869, a multitargeted receptor tyrosine kinase inhibitor: inhibition of FLT3 phosphorylation and signaling in acute myeloid leukemia. Blood 2007; 109(8):3400-3408.

5. Zhou J, Khng J et al. In vivo activity of ABT-869, a multi-target kinase inhibitor, against acute myeloid leukemia with wild-type FLT3 receptor. Leuk Res 2008; 32(7):1091-1100.

6. Ikeda AK, Judelson DR et al. ABT-869 inhibits the proliferation of Ewing Sarcoma cells and suppresses platelet-derived growth factor receptor beta and c-KIT signaling pathways. Mol Cancer Ther 2010; 9(3):653-660.

7. Wong CI, Koh TS et al. Phase I and biomarker study of ABT-869, a multiple receptor tyrosine kinase inhibitor, in patients with refractory solid malignancies. J Clin Oncol 2009; 27(28):4718-4726.

8. Tan EH, Goss GD et al. Phase 2 trial of Linifanib (ABT-869) in patients with advanced non-small cell lung cancer. J Thorac Oncol 2011; 6(8):1418-1425.

9. Tannir NM, Wong YN et al. Phase 2 trial of linifanib (ABT-869) in patients with advanced renal cell cancer after sunitinib failure. Eur J Cancer 2011; 47(18):2706-2714.