Linifanib (ABT-869)
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MedKoo CAT#: 200060

CAS#: 796967-16-3

Description: Linifanib, also known as ABT-869, 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).


Chemical Structure

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Linifanib (ABT-869)
CAS# 796967-16-3

Theoretical Analysis

MedKoo Cat#: 200060
Name: Linifanib (ABT-869)
CAS#: 796967-16-3
Chemical Formula: C21H18FN5O
Exact Mass: 375.14954
Molecular Weight: 375.4
Elemental Analysis: C, 67.19; H, 4.83; F, 5.06; N, 18.66; O, 4.26

Price and Availability

Size Price Availability Quantity
10.0mg USD 90.0 Same day
25.0mg USD 150.0 Same day
50.0mg USD 250.0 Same day
100.0mg USD 450.0 Same day
200.0mg USD 750.0 Same day
500.0mg USD 1450.0 Same day
1.0g USD 2250.0 2 Weeks
2.0g USD 3750.0 2 Weeks
5.0g USD 6950.0 2 Weeks
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Synonym: ABT869; ABT 869; ABT-869; Linifanib

IUPAC/Chemical Name: N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N1-(2-fluoro-5-methylphenyl) urea

InChi Key: ACPCMBPQKQTAQY-UHFFFAOYSA-N

InChi Code: InChI=1S/C21H18FN5O/c1-12-5-10-16(22)18(11-12)27(21(24)28)14-8-6-13(7-9-14)15-3-2-4-17-19(15)20(23)26-25-17/h2-11H,1H3,(H2,24,28)(H3,23,25,26)

SMILES Code: O=C(N)N(C1=CC=C(C2=CC=CC3=C2C(N)=NN3)C=C1)C4=CC(C)=CC=C4F

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: soluble in DMSO, not soluble in water.

Shelf Life: >5 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Linifanib (ABT-869) is a multi-target inhibitor of VEGFR and PDGFR family with IC50s of 4, 3, 66, and 4 nM for KDR, FLT1, PDGFRβ, and FLT3, respectively.
In vitro activity: Linifanib is effective at inhibiting phosphorylation of FLT3 in Ba/F3 FLT3 ITD cell lines at a concentration of 10nM (Fig. 4a). In addition, Linifanib reduced phosphorylation of AKT at Ser473 after treatment with 10nM of Linifanib (Fig. 4b). To test whether GSK3β phosphorylation was affected after treatment with Linifanib, the ITD mutant cells were treated with 10nM Linifanib phosphorylation of GSK 3β at Ser9 (Fig. 4c) or GSK 3α at Ser21 (data not shown) was examined. Treatment with 10nM Linifanib resulted in decreased phosphorylation of GSK3β Ser 9 as early as 60 minutes (Fig. 4c). Reference: Mol Cancer Ther. 2011 Jun; 10(6): 949–959. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3112478/
In vivo activity: To analyze the potential effects of ABT-869 on a metastatic model of Ewing sarcoma, GFP/Luciferase-expressing A4573 and TC71 cells (A4573-GFP/LUC, TC71-GFP/LUC) were generated through lentiviral transduction followed by sorting for GFP. The sorted cells were cultured and injected through the tail vein into female NOD/SCID mice. Six mice were analyzed per treatment group. Engraftment and disease progression were monitored by acquiring in vivo bioluminescent images at least once per week. The mice began treatment the day after injection. Kaplan-Meier analysis demonstrated a survival benefit in the treatment group compared to the vehicle control group with both the A4573 GFP/LUC cell lines (p=0.015) (Figure 6A) and TC71-GFP/LUC (p=0.002) (Figure 6B). Furthermore, the tagged cells showed evidence of more aggressive disease in mice treated with ABT-869 compared to untreated mice (Figure 6C). As previously observed, the mice tolerated the ABT-869 well, maintained their normal activity levels and weight (16). These results suggest that survival is prolonged and disease progression is suppressed in mice treated with ABT-869. Reference: Mol Cancer Ther. 2010 Mar; 9(3): 653–660. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2837519/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 19.08 50.83
DMSO:PBS (pH 7.2) (1:5) 0.2 0.53
DMF 20.0 53.28

Preparing Stock Solutions

The following data is based on the product molecular weight 375.4 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Hernandez-Davies JE, Zape JP, Landaw EM, Tan X, Presnell A, Griffith D, Heinrich MC, Glaser KB, Sakamoto KM. The multitargeted receptor tyrosine kinase inhibitor linifanib (ABT-869) induces apoptosis through an Akt and glycogen synthase kinase 3β-dependent pathway. Mol Cancer Ther. 2011 Jun;10(6):949-59. doi: 10.1158/1535-7163.MCT-10-0904. Epub 2011 Apr 6. PMID: 21471285; PMCID: PMC3112478. 2. 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. doi: 10.1182/blood-2006-06-029579. Epub 2007 Jan 5. PMID: 17209055; PMCID: PMC1852258. 3. Chen J, Guo J, Chen Z, Wang J, Liu M, Pang X. Linifanib (ABT-869) Potentiates the Efficacy of Chemotherapeutic Agents through the Suppression of Receptor Tyrosine Kinase-Mediated AKT/mTOR Signaling Pathways in Gastric Cancer. Sci Rep. 2016 Jul 8;6:29382. doi: 10.1038/srep29382. PMID: 27387652; PMCID: PMC4937412. 4. Ikeda AK, Judelson DR, Federman N, Glaser KB, Landaw EM, Denny CT, Sakamoto KM. 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 Mar;9(3):653-60. doi: 10.1158/1535-7163.MCT-09-0812. Epub 2010 Mar 2. PMID: 20197394; PMCID: PMC2837519.
In vitro protocol: 1. Hernandez-Davies JE, Zape JP, Landaw EM, Tan X, Presnell A, Griffith D, Heinrich MC, Glaser KB, Sakamoto KM. The multitargeted receptor tyrosine kinase inhibitor linifanib (ABT-869) induces apoptosis through an Akt and glycogen synthase kinase 3β-dependent pathway. Mol Cancer Ther. 2011 Jun;10(6):949-59. doi: 10.1158/1535-7163.MCT-10-0904. Epub 2011 Apr 6. PMID: 21471285; PMCID: PMC3112478. 2. 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. doi: 10.1182/blood-2006-06-029579. Epub 2007 Jan 5. PMID: 17209055; PMCID: PMC1852258.
In vivo protocol: 1. Chen J, Guo J, Chen Z, Wang J, Liu M, Pang X. Linifanib (ABT-869) Potentiates the Efficacy of Chemotherapeutic Agents through the Suppression of Receptor Tyrosine Kinase-Mediated AKT/mTOR Signaling Pathways in Gastric Cancer. Sci Rep. 2016 Jul 8;6:29382. doi: 10.1038/srep29382. PMID: 27387652; PMCID: PMC4937412. 2. Ikeda AK, Judelson DR, Federman N, Glaser KB, Landaw EM, Denny CT, Sakamoto KM. 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 Mar;9(3):653-60. doi: 10.1158/1535-7163.MCT-09-0812. Epub 2010 Mar 2. PMID: 20197394; PMCID: PMC2837519.

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 1: Ikeda AK, Judelson DR, Federman N, Glaser KB, Landaw EM, Denny CT, Sakamoto KM. 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 Mar;9(3):653-60. Epub 2010 Mar 2. PubMed PMID: 20197394; PubMed Central PMCID: PMC2837519.

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.



Additional Information

 
 
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 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. ).
Phase 2 trial of Linifanib (ABT-869) in patients with advanced non-small cell lung cancer.
(source: J Thorac Oncol. 2011 Aug;6(8):1418-25. ).