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Linifanib

Description of Linifanib: Linifanib is an orally bioavailable, small-molecule receptor tyrosine kinase (RTK) inhibitor with potential antineoplastic activity. Linifanib inhibits members of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor families; it exhibits much less activity against unrelated RTKs, soluble tyrosine kinases, or serine/threonine kinases. This agent does not have a general antiproliferative effect due to its high dose requirement. However, linifanib may exhibit potent antiproliferative and apoptotic effects on tumor cells whose proliferation is dependent on mutant kinases, such as fms-related tyrosine kinase receptor-3 (FLT3). Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus)

Current developer:   Abbott Laboratories.

Phase 2 trial of linifanib (ABT-869) in patients with advanced renal cell cancer after sunitinib failure.  Linifanib demonstrated clinically meaningful activity in patients with advanced RCC after sunitinib failure. At 0.25 mg/kg/day, significant dose modifications were required. An alternative, fixed-dosing strategy is being evaluated in other trials. (source: Eur J Cancer. 2011 Dec;47(18):2706-14).

Phase 2 trial of Linifanib (ABT-869) in patients with advanced non-small cell lung cancer. Linifanib is active in advanced non-small cell lung cancer as second- or third-line therapy. Increased adverse event rates were observed at the high dose of linifanib. (source: J Thorac Oncol. 2011 Aug;6(8):1418-25.).

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2: Wong CI, Koh TS, Soo R, Hartono S, Thng CH, McKeegan E, Yong WP, Chen CS, Lee SC, Wong J, Lim R, Sukri N, Lim SE, Ong AB, Steinberg J, Gupta N, Pradhan R, Humerickhouse R, Goh BC. Phase I and biomarker study of ABT-869, a multiple receptor tyrosine kinase inhibitor, in patients with refractory solid malignancies. J Clin Oncol. 2009 Oct 1;27(28):4718-26. Epub 2009 Aug 31. PubMed PMID: 19720910.

3: Zhou J, Goh BC, Albert DH, Chen CS. ABT-869, a promising multi-targeted tyrosine kinase inhibitor: from bench to bedside. J Hematol Oncol. 2009 Jul 30;2:33. PubMed PMID: 19642998; PubMed Central PMCID: PMC2729745.

4: Tomillero A, Moral MA. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2009 Mar;31(2):107-46. PubMed PMID: 19455266.

5: Franklin PH, Banfor PN, Tapang P, Segreti JA, Widomski DL, Larson KJ, Noonan WT, Gintant GA, Davidsen SK, Albert DH, Fryer RM, Cox BF. Effect of the multitargeted receptor tyrosine kinase inhibitor, ABT-869 [N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N'-(2-fluoro-5-methylphenyl)urea], on blood pressure in conscious rats and mice: reversal with antihypertensive agents and effect on tumor growth inhibition. J Pharmacol Exp Ther. 2009 Jun;329(3):928-37. Epub 2009 Mar 2. PubMed PMID: 19255283.

6: Banfor PN, Franklin PA, Segreti JA, Widomski DL, Davidsen SK, Albert DH, Cox BF, Fryer RM, Gintant GA. ETA receptor blockade with atrasentan prevents hypertension with the multitargeted tyrosine kinase inhibitor ABT-869 in telemetry-instrumented rats. J Cardiovasc Pharmacol. 2009 Feb;53(2):173-8. PubMed PMID: 19188829.

7: Zhou J, Bi C, Janakakumara JV, Liu SC, Chng WJ, Tay KG, Poon LF, Xie Z, Palaniyandi S, Yu H, Glaser KB, Albert DH, Davidsen SK, Chen CS. Enhanced activation of STAT pathways and overexpression of survivin confer resistance to FLT3 inhibitors and could be therapeutic targets in AML. Blood. 2009 Apr 23;113(17):4052-62. Epub 2009 Jan 14. PubMed PMID: 19144991.

8: Jasinghe VJ, Xie Z, Zhou J, Khng J, Poon LF, Senthilnathan P, Glaser KB, Albert DH, Davidsen SK, Chen CS. ABT-869, a multi-targeted tyrosine kinase inhibitor, in combination with rapamycin is effective for subcutaneous hepatocellular carcinoma xenograft. J Hepatol. 2008 Dec;49(6):985-97. Epub 2008 Oct 1. PubMed PMID: 18930332.

9: Wu H, Zhang J, Norem K, El-Shourbagy TA. Simultaneous determination of a hydrophobic drug candidate and its metabolite in human plasma with salting-out assisted liquid/liquid extraction using a mass spectrometry friendly salt. J Pharm Biomed Anal. 2008 Dec 1;48(4):1243-8. Epub 2008 Sep 9. PubMed PMID: 18926659.

10: Zhou J, Khng J, Jasinghe VJ, Bi C, Neo CH, Pan M, Poon LF, Xie Z, Yu H, Yeoh AE, Lu Y, Glaser KB, Albert DH, Davidsen SK, Chen CS. In vivo activity of ABT-869, a multi-target kinase inhibitor, against acute myeloid leukemia with wild-type FLT3 receptor. Leuk Res. 2008 Jul;32(7):1091-100. Epub 2007 Dec 26. PubMed PMID: 18160102.

11: Bayes M, Rabasseda X, Prous JR. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2007 Oct;29(8):547-83. PubMed PMID: 18040531.

12: Zhou J, Pan M, Xie Z, Loh SL, Bi C, Tai YC, Lilly M, Lim YP, Han JH, Glaser KB, Albert DH, Davidsen SK, Chen CS. Synergistic antileukemic effects between ABT-869 and chemotherapy involve downregulation of cell cycle-regulated genes and c-Mos-mediated MAPK pathway. Leukemia. 2008 Jan;22(1):138-46. Epub 2007 Oct 18. PubMed PMID: 17943175.

13: Bayés M, Rabasseda X, Prous JR. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2007 Jun;29(5):359-73. PubMed PMID: 17805439.

14: Dai Y, Hartandi K, Ji Z, Ahmed AA, Albert DH, Bauch JL, Bouska JJ, Bousquet PF, Cunha GA, Glaser KB, Harris CM, Hickman D, Guo J, Li J, Marcotte PA, Marsh KC, Moskey MD, Martin RL, Olson AM, Osterling DJ, Pease LJ, Soni NB, Stewart KD, Stoll VS, Tapang P, Reuter DR, Davidsen SK, Michaelides MR. 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 Apr 5;50(7):1584-97. Epub 2007 Mar 8. PubMed PMID: 17343372.

15: Shankar DB, Li J, Tapang P, Owen McCall J, Pease LJ, Dai Y, Wei RQ, Albert DH, Bouska JJ, Osterling DJ, Guo J, Marcotte PA, Johnson EF, Soni N, Hartandi K, Michaelides MR, Davidsen SK, Priceman SJ, Chang JC, Rhodes K, Shah N, Moore TB, Sakamoto KM, Glaser KB. ABT-869, a multitargeted receptor tyrosine kinase inhibitor: inhibition of FLT3 phosphorylation and signaling in acute myeloid leukemia. Blood. 2007 Apr 15;109(8):3400-8. Epub 2007 Jan 5. PubMed PMID: 17209055; PubMed Central PMCID: PMC1852258.

16: Wang PG, Zhang J, Gage EM, Schmidt JM, Rodila RC, Ji QC, El-Shourbagy TA. A high-throughput liquid chromatography/tandem mass spectrometry method for simultaneous quantification of a hydrophobic drug candidate and its hydrophilic metabolite in human urine with a fully automated liquid/liquid extraction. Rapid Commun Mass Spectrom. 2006;20(22):3456-64. PubMed PMID: 17066370.

17: Rodila RC, Kim JC, Ji QC, El-Shourbagy TA. A high-throughput, fully automated liquid/liquid extraction liquid chromatography/mass spectrometry method for the quantitation of a new investigational drug ABT-869 and its metabolite A-849529 in human plasma samples. Rapid Commun Mass Spectrom. 2006;20(20):3067-75. PubMed PMID: 16969771.

18: Li L, Lin X, Shoemaker AR, Albert DH, Fesik SW, Shen Y. Hypoxia-inducible factor-1 inhibition in combination with temozolomide treatment exhibits robust antitumor efficacy in vivo. Clin Cancer Res. 2006 Aug 1;12(15):4747-54. PubMed PMID: 16899626.

19: Guo J, Marcotte PA, McCall JO, Dai Y, Pease LJ, Michaelides MR, Davidsen SK, Glaser KB. 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 Apr;5(4):1007-13. PubMed PMID: 16648572.

20: Albert DH, Tapang P, Magoc TJ, Pease LJ, Reuter DR, Wei RQ, Li J, Guo J, Bousquet PF, Ghoreishi-Haack NS, Wang B, Bukofzer GT, Wang YC, Stavropoulos JA, Hartandi K, Niquette AL, Soni N, Johnson EF, McCall JO, Bouska JJ, Luo Y, Donawho CK, Dai Y, Marcotte PA, Glaser KB, Michaelides MR, Davidsen SK. Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor. Mol Cancer Ther. 2006 Apr;5(4):995-1006. PubMed PMID: 16648571.

21: Carlson DM, Steinberg JL, Gordon G. Targeting the unmet medical need: the Abbott Laboratories oncology approach. Clin Adv Hematol Oncol. 2005 Sep;3(9):703-10. PubMed PMID: 16224444.