Axitinib
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MedKoo CAT#: 200400

CAS#: 319460-85-0

Description: Axitinib, also known as AG013736, is an orally bioavailable tyrosine kinase inhibitor. Axitinib inhibits the proangiogenic cytokines vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptor (PDGF), thereby exerting an anti-angiogenic effect. A xitinib has received FDA (27 January 2012), EMA (13 September 2012), MHRA (3 September 2012) and TGA (26 July 2012) approval for use as a treatment for renal cell carcinoma.


Chemical Structure

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Axitinib
CAS# 319460-85-0

Theoretical Analysis

MedKoo Cat#: 200400
Name: Axitinib
CAS#: 319460-85-0
Chemical Formula: C22H18N4OS
Exact Mass: 386.12013
Molecular Weight: 386.47
Elemental Analysis: C, 68.37; H, 4.69; N, 14.50; O, 4.14; S, 8.30

Price and Availability

Size Price Availability Quantity
500.0mg USD 150.0 Same Day
1.0g USD 250.0 Same Day
2.0g USD 450.0 Same Day
5.0g USD 750.0 Same Day
10.0g USD 1250.0 Same Day
20.0g USD 2250.0 Same Day
50.0g USD 4950.0 Same Day
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Synonym: AG013736; AG 013736; AG-013736; Axitinib; Brand name: Inlyta.

IUPAC/Chemical Name: (E)-N-methyl-2-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)benzamide

InChi Key: RITAVMQDGBJQJZ-FMIVXFBMSA-N

InChi Code: InChI=1S/C22H18N4OS/c1-23-22(27)18-7-2-3-8-21(18)28-16-10-11-17-19(25-26-20(17)14-16)12-9-15-6-4-5-13-24-15/h2-14H,1H3,(H,23,27)(H,25,26)/b12-9+

SMILES Code: O=C(NC)C1=CC=CC=C1SC2=CC3=C(C=C2)C(/C=C/C4=NC=CC=C4)=NN3

Appearance: white to off-white 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 in water

Shelf Life: >2 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: Axitinib is a multi-targeted tyrosine kinase inhibitor with IC50s of 0.1, 0.2, 0.1-0.3, 1.6 nM for VEGFR1, VEGFR2, VEGFR3 and PDGFRβ, respectively.
In vitro activity: In an in vitro study, axitinib significantly inhibited proliferation and migration, and increased apoptosis, of EOC cells in a dose-dependent manner. Initially, cell viability experiments presented that axitinib showed cytotoxic activity in all EOC cells. In addition, axitinib-induced apoptosis was confirmed in EOC cell lines. However, in Western blot confirming expression of VEGFR and its downstream signaling in EOC cell lines, axitinib-induced inhibitory effects in VEGFR2, phosphorylation of AKT, and ERK were not observed in HeyA8-MDR. Unlike A2780 and HeyA8, the migration assay showed no effect of axitinib on HeyA8-MDR. Based on these results, it is hypothesized that axitinib inhibits EOC cells by targeting multiple pathways including angiogenesis, AKT, and ERK signaling pathways. Reference: Sci Rep. 2020; 10: 4904. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078214/
In vivo activity: In the GIST-T1 xenograft mouse model, axitinib exhibited dose-dependent tumor growth suppression and the TGI (tumor inhibition rate) was 53% at 100 mg/kg/day dosage [Figure 5(a)]. In the GIST-5R xenograft mouse model, 100 mg/kg/day dosage of axitinib could almost completely block the tumor progression and showed a TGI of 88%, whereas the same dosage of imatinib showed limited effect on tumor growth [Figure 5(b)]. As expected, reduced phosphorylation of cKIT and related downstream mediators such as STAT3, AKT, and ERK in tumors were observed compared with the vehicle-treated controls (Supplemental Figure 4). Furthermore, this study found that at 100 mg/kg dosage, aurora kinase started to be inhibited, which might help to enhance the antitumor efficacy of axitinib in vivo (Supplemental Figure 4). These data were also consistent with the results observed in the cell cycle arrest assays and centrosome separation experiments [Figure 4(b) and Supplemental Figure 2]. Reference: Ther Adv Med Oncol. 2019; 11: 1758835919849757. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535728/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 14.75 38.17
DMF 0.25 0.65

Preparing Stock Solutions

The following data is based on the product molecular weight 386.47 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. Paik ES, Kim TH, Cho YJ, Ryu J, Choi JJ, Lee YY, Kim TJ, Choi CH, Kim WY, Sa JK, Lee JK, Kim BG, Bae DS, Han HD, Ahn HJ, Lee JW. Preclinical assessment of the VEGFR inhibitor axitinib as a therapeutic agent for epithelial ovarian cancer. Sci Rep. 2020 Mar 17;10(1):4904. doi: 10.1038/s41598-020-61871-w. PMID: 32184452; PMCID: PMC7078214. 2. Kerr LT, Donoghue JF, Wilding AL, Johns TG. Axitinib Has Antiangiogenic and Antitumorigenic Activity in Myxoid Liposarcoma. Sarcoma. 2016;2016:3484673. doi: 10.1155/2016/3484673. Epub 2016 Oct 16. PMID: 27822137; PMCID: PMC5086398. 3. Liu F, Zou F, Chen C, Yu K, Liu X, Qi S, Wu J, Hu C, Hu Z, Liu J, Liu X, Wang L, Ge J, Wang W, Ren T, Bai M, Cai Y, Xiao X, Qian F, Tang J, Liu Q, Liu J. Axitinib overcomes multiple imatinib resistant cKIT mutations including the gatekeeper mutation T670I in gastrointestinal stromal tumors. Ther Adv Med Oncol. 2019 May 17;11:1758835919849757. doi: 10.1177/1758835919849757. PMID: 31205508; PMCID: PMC6535728. 4. Van der Veken B, De Meyer GRY, Martinet W. Axitinib attenuates intraplaque angiogenesis, haemorrhages and plaque destabilization in mice. Vascul Pharmacol. 2018 Jan;100:34-40. doi: 10.1016/j.vph.2017.10.004. Epub 2017 Oct 31. PMID: 29079346.
In vitro protocol: 1. Paik ES, Kim TH, Cho YJ, Ryu J, Choi JJ, Lee YY, Kim TJ, Choi CH, Kim WY, Sa JK, Lee JK, Kim BG, Bae DS, Han HD, Ahn HJ, Lee JW. Preclinical assessment of the VEGFR inhibitor axitinib as a therapeutic agent for epithelial ovarian cancer. Sci Rep. 2020 Mar 17;10(1):4904. doi: 10.1038/s41598-020-61871-w. PMID: 32184452; PMCID: PMC7078214. 2. Kerr LT, Donoghue JF, Wilding AL, Johns TG. Axitinib Has Antiangiogenic and Antitumorigenic Activity in Myxoid Liposarcoma. Sarcoma. 2016;2016:3484673. doi: 10.1155/2016/3484673. Epub 2016 Oct 16. PMID: 27822137; PMCID: PMC5086398.
In vivo protocol: 1. Liu F, Zou F, Chen C, Yu K, Liu X, Qi S, Wu J, Hu C, Hu Z, Liu J, Liu X, Wang L, Ge J, Wang W, Ren T, Bai M, Cai Y, Xiao X, Qian F, Tang J, Liu Q, Liu J. Axitinib overcomes multiple imatinib resistant cKIT mutations including the gatekeeper mutation T670I in gastrointestinal stromal tumors. Ther Adv Med Oncol. 2019 May 17;11:1758835919849757. doi: 10.1177/1758835919849757. PMID: 31205508; PMCID: PMC6535728. 2. Van der Veken B, De Meyer GRY, Martinet W. Axitinib attenuates intraplaque angiogenesis, haemorrhages and plaque destabilization in mice. Vascul Pharmacol. 2018 Jan;100:34-40. doi: 10.1016/j.vph.2017.10.004. Epub 2017 Oct 31. PMID: 29079346.

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1: Gunnarsson O, Pfanzelter NR, Cohen RB, Keefe SM. Evaluating the safety and efficacy of axitinib in the treatment of advanced renal cell carcinoma. Cancer Manag Res. 2015 Feb 11;7:65-73. doi: 10.2147/CMAR.S74202. eCollection 2015. Review. PubMed PMID: 25709499; PubMed Central PMCID: PMC4334173.

2: Tzogani K, Skibeli V, Westgaard I, Dalhus M, Thoresen H, Slot KB, Damkier P, Hofland K, Borregaard J, Ersbøll J, Salmonson T, Pieters R, Sylvester R, Mickisch G, Bergh J, Pignatti F. The European Medicines Agency Approval of Axitinib (Inlyta) for the Treatment of Advanced Renal Cell Carcinoma After Failure of Prior Treatment With Sunitinib or a Cytokine: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use. Oncologist. 2015 Feb;20(2):196-201. Epub 2015 Jan 23. Review. PubMed PMID: 25616431; PubMed Central PMCID: PMC4319625.

3: Borst DL, Arruda LS, MacLean E, Pithavala YK, Morgado JE. Common questions regarding clinical use of axitinib in advanced renal cell carcinoma. Am J Health Syst Pharm. 2014 Jul 1;71(13):1092-6. doi: 10.2146/ajhp130581. Review. PubMed PMID: 24939498.

4: Verzoni E, Grassi P, Testa I, Iacovelli R, Biondani P, Garanzini E, De Braud F, Procopio G. Targeted treatments in advanced renal cell carcinoma: focus on axitinib. Pharmgenomics Pers Med. 2014 Mar 27;7:107-16. doi: 10.2147/PGPM.S37098. eCollection 2014. Review. PubMed PMID: 24715765; PubMed Central PMCID: PMC3977458.

5: Bracarda S, Castellano D, Procopio G, Sepúlveda JM, Sisani M, Verzoni E, Schmidinger M. Axitinib safety in metastatic renal cell carcinoma: suggestions for daily clinical practice based on case studies. Expert Opin Drug Saf. 2014 Apr;13(4):497-510. doi: 10.1517/14740338.2014.888413. Review. PubMed PMID: 24641566.

6: Akaza H, Fukuyama T. Axitinib for the treatment of advanced renal cell carcinoma. Expert Opin Pharmacother. 2014 Feb;15(2):283-97. doi: 10.1517/14656566.2014.868436. Epub 2013 Dec 13. Review. PubMed PMID: 24328549.

7: Gross-Goupil M, François L, Quivy A, Ravaud A. Axitinib: a review of its safety and efficacy in the treatment of adults with advanced renal cell carcinoma. Clin Med Insights Oncol. 2013 Oct 29;7:269-77. doi: 10.4137/CMO.S10594. Review. PubMed PMID: 24250243; PubMed Central PMCID: PMC3825605.

8: Chen Y, Tortorici MA, Garrett M, Hee B, Klamerus KJ, Pithavala YK. Clinical pharmacology of axitinib. Clin Pharmacokinet. 2013 Sep;52(9):713-25. doi: 10.1007/s40262-013-0068-3. Review. PubMed PMID: 23677771.

9: Qi WX, He AN, Shen Z, Yao Y. Incidence and risk of hypertension with a novel multi-targeted kinase inhibitor axitinib in cancer patients: a systematic review and meta-analysis. Br J Clin Pharmacol. 2013 Sep;76(3):348-57. doi: 10.1111/bcp.12149. Review. PubMed PMID: 23617405; PubMed Central PMCID: PMC3769663.

10: King JW, Lee SM. Axitinib for the treatment of advanced non-small-cell lung cancer. Expert Opin Investig Drugs. 2013 Jun;22(6):765-73. doi: 10.1517/13543784.2013.775243. Epub 2013 Mar 1. Review. PubMed PMID: 23452008.

Axitinib

500.0mg / USD 150.0


Additional Information

Axitinib (also known as AG013736) is a small molecule tyrosine kinase inhibitor under development by Pfizer. It inhibits multiple targets, including VEGFR-1, VEGFR-2, VEGFR-3, platelet derived growth factor receptor (PDGFR), and cKIT (CD117). It has been shown to significantly inhibit growth of breast cancer in xenograft models  and has been successful in trials with renal cell carcinoma (RCC)  and several other tumor types.
Axitinib is a white to light-yellow powder with a pKa of 4.8. The solubility of axitinib in aqueous media over the range pH 1.1 to pH 7.8 is in excess of 0.2 μg/mL. The partition coefficient (n-octanol/water) is 3.5.
  
A Phase II clinical trial showed good response in combination chemotherapy with Gemcitabine for advanced pancreatic cancer. However, Pfizer reported on January 30, 2009 that Phase III clinical trials of the drug when used in combination with Gemcitabine showed no evidence of improved survival rates over treatments using Gemcitabine alone for advanced pancreatic cancer and halted the trial.  see http://en.wikipedia.org/wiki/Axitinib.