Sunitinib malate
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MedKoo CAT#: 100790

CAS#: 341031-54-7 (malate)

Description: Sunitinib, also known as SU11248, is the orally bioavailable malate salt of an indolinone-based tyrosine kinase inhibitor with potential antineoplastic activity. Sunitinib was approved by the FDA for the treatment of renal cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal tumor (GIST) on January 26, 2006. Sunitinib blocks the tyrosine kinase activities of vascular endothelial growth factor receptor 2 (VEGFR2), platelet-derived growth factor receptor b (PDGFRb), and c-kit, thereby inhibiting angiogenesis and cell proliferation.


Chemical Structure

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Sunitinib malate
CAS# 341031-54-7 (malate)

Theoretical Analysis

MedKoo Cat#: 100790
Name: Sunitinib malate
CAS#: 341031-54-7 (malate)
Chemical Formula: C26H33FN4O7
Exact Mass:
Molecular Weight: 532.56
Elemental Analysis: C, 58.64; H, 6.25; F, 3.57; N, 10.52; O, 21.03

Price and Availability

Size Price Availability Quantity
2.0g USD 150.0 Ready to ship
5.0g USD 250.0 Ready to ship
50.0g USD 1650.0 Ready to ship
100.0g USD 2650.0 Ready to ship
500.0g USD 3950.0 2 Weeks
1.0kg USD 6450.0 2 Weeks
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Related CAS #: 341031-54-7 (malate)   557795-19-4 (free base)   342641-94-5   1126641-10-8 (maleate)   1221149-36-5 (acetate)   1327155-72-5 (HCl)   1275588-72-1 (mesylate)   1332306-95-2 (oxalate)    

Synonym: SU11248; SU-11248; SU 11248; SU011248; Sunitinib malate; Sutent.

IUPAC/Chemical Name: (Z)-N-(2-(diethylamino)ethyl)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide malate

InChi Key: LBWFXVZLPYTWQI-HBPAQXCTSA-N

InChi Code: InChI=1S/C22H27FN4O2.C4H6O5/c1-5-27(6-2)10-9-24-22(29)20-13(3)19(25-14(20)4)12-17-16-11-15(23)7-8-18(16)26-21(17)28;5-2(4(8)9)1-3(6)7/h7-8,11-12,25H,5-6,9-10H2,1-4H3,(H,24,29)(H,26,28);2,5H,1H2,(H,6,7)(H,8,9)/b17-12-;

SMILES Code: O=C(C1=C(C)NC(/C=C2C(NC3=C\2C=C(F)C=C3)=O)=C1C)NCCN(CC)CC.OC(CC(O)=O)C(O)=O

Appearance: Yellow solid powder

Purity: >99% (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: Sunitinib Malate is a receptor tyrosine kinase inhibitor with IC50s of 80 nM and 2 nM for VEGFR2 and PDGFRβ, respectively.
In vitro activity: In order to determine the impact of sunitinib on ectopic endometrial cells, ectopic and normal endometrial cells were treated with sunitinib at appointed concentrations of 0, 1, 2, 4, 8, and 16 uM for 48 hours. The MTT assay revealed that the half maximal inhibitory concentration (IC50) of normal endometrial cells to sunitinib (IC50 = 7.9 μM) was significantly higher, when compared to ectopic endometrial cells (IC50 = 3.32 μM), suggesting that sunitinib has no effect on the normal endometrium within the therapeutic concentration range, since it is on the ectopic endometrium in vitro (Figure 2A). Then, it was measured that sunitinib reduced the cell apoptosis by nuclear-fluorescence staining. These results show that the number of apoptotic cells in the ectopic endometrial group (100x) increased with the increase in sunitinib concentration (Figure 2B). Furthermore, in order to confirm the results above, the cell apoptosis was determined by flow cytometry. The cell apoptosis rate (FITC + plus FITC+/PI+) in ectopic endometrial cells was 51.9%±8.3% and 78.8% ± 3.2% at a sunitinib concentration of 4 μM and 8 μM, respectively, and both were significantly higher than that in normal endometrial cells, with 0.2% ± 1.2% (vs ectopic endometrial cells, P < .0001, t = 26.89) and 68.1% ± 2.1% (vs ectopic endometrial cells, P = .025, t = 3.49), respectively (Figure 2C). These results demonstrate that sunitinib can affect the cell proliferation and apoptosis of ectopic endometrial cells in a dose-dependent manner. Reference: J Clin Lab Anal. 2020 Nov;34(11):e23482. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676178/
In vivo activity: Mice were treated orally with sunitinib (7.5 mg/kg/day) for 2 weeks. Sunitinib did not affect body weight, but increased plasma ALT activity 6-fold. Protein and mRNA expression of several subunits of mitochondrial enzyme complexes were decreased in mitochondria from sunitinib-treated mice. Protein expression of PGC-1α, citrate synthase activity and mtDNA copy number were all decreased in livers of sunitinib-treated mice, indicating impaired mitochondrial proliferation. Caspase 3 activation and TUNEL-positive hepatocytes were increased in livers of sunitinib-treated mice, indicating hepatocyte apoptosis. In conclusion, sunitinib caused concentration-dependent toxicity in isolated mitochondria at concentrations reached in livers in vivo and inhibited hepatic mitochondrial proliferation. Daily mitochondrial insults and impaired mitochondrial proliferation most likely explain hepatocellular injury observed in mice treated with sunitinib. Reference: Toxicology. 2018 Nov 1;409:13-23. https://www.sciencedirect.com/science/article/abs/pii/S0300483X18301574?via%3Dihub

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMF 1.0 1.88
DMSO 28.33 53.2
DMSO:PBS (pH 7.2) (1:3) 0.25 0.47

Preparing Stock Solutions

The following data is based on the product molecular weight 532.56 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. Li J, Abudula M, Fan X, Wang F, Chen Y, Liu L. Sunitinib induces primary ectopic endometrial cell apoptosis through up-regulation of STAT1 in vitro. J Clin Lab Anal. 2020 Nov;34(11):e23482. doi: 10.1002/jcla.23482. Epub 2020 Aug 5. PMID: 32761670; PMCID: PMC7676178. 2. Mendel DB, Laird AD, Xin X, Louie SG, Christensen JG, Li G, Schreck RE, Abrams TJ, Ngai TJ, Lee LB, Murray LJ, Carver J, Chan E, Moss KG, Haznedar JO, Sukbuntherng J, Blake RA, Sun L, Tang C, Miller T, Shirazian S, McMahon G, Cherrington JM. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res. 2003 Jan;9(1):327-37. PMID: 12538485. 3. Paech F, Abegg VF, Duthaler U, Terracciano L, Bouitbir J, Krähenbühl S. Sunitinib induces hepatocyte mitochondrial damage and apoptosis in mice. Toxicology. 2018 Nov 1;409:13-23. doi: 10.1016/j.tox.2018.07.009. Epub 2018 Jul 18. PMID: 30031043.
In vitro protocol: 1. Li J, Abudula M, Fan X, Wang F, Chen Y, Liu L. Sunitinib induces primary ectopic endometrial cell apoptosis through up-regulation of STAT1 in vitro. J Clin Lab Anal. 2020 Nov;34(11):e23482. doi: 10.1002/jcla.23482. Epub 2020 Aug 5. PMID: 32761670; PMCID: PMC7676178. 2. Mendel DB, Laird AD, Xin X, Louie SG, Christensen JG, Li G, Schreck RE, Abrams TJ, Ngai TJ, Lee LB, Murray LJ, Carver J, Chan E, Moss KG, Haznedar JO, Sukbuntherng J, Blake RA, Sun L, Tang C, Miller T, Shirazian S, McMahon G, Cherrington JM. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res. 2003 Jan;9(1):327-37. PMID: 12538485.
In vivo protocol: 1. Mendel DB, Laird AD, Xin X, Louie SG, Christensen JG, Li G, Schreck RE, Abrams TJ, Ngai TJ, Lee LB, Murray LJ, Carver J, Chan E, Moss KG, Haznedar JO, Sukbuntherng J, Blake RA, Sun L, Tang C, Miller T, Shirazian S, McMahon G, Cherrington JM. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res. 2003 Jan;9(1):327-37. PMID: 12538485. 2. Paech F, Abegg VF, Duthaler U, Terracciano L, Bouitbir J, Krähenbühl S. Sunitinib induces hepatocyte mitochondrial damage and apoptosis in mice. Toxicology. 2018 Nov 1;409:13-23. doi: 10.1016/j.tox.2018.07.009. Epub 2018 Jul 18. PMID: 30031043.

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1: Bisht S, Feldmann G, Brossart P. Pharmacokinetics and pharmacodynamics of sunitinib for the treatment of advanced pancreatic neuroendocrine tumors. Expert Opin Drug Metab Toxicol. 2013 Jun;9(6):777-88. doi: 10.1517/17425255.2013.791281. Epub 2013 Apr 16. Review. PubMed PMID: 23590356.

2: Breaker K, Naam M, La Rosa FG, Flaig IP, Flaig TW. Skin cancer associated with the use of sorafenib and sunitinib for renal cell carcinoma. Dermatol Surg. 2013 Jul;39(7):981-7. doi: 10.1111/dsu.12184. Epub 2013 Mar 6. Review. PubMed PMID: 23464361.

3: Mankal P, O'Reilly E. Sunitinib malate for the treatment of pancreas malignancies--where does it fit? Expert Opin Pharmacother. 2013 Apr;14(6):783-92. doi: 10.1517/14656566.2013.776540. Epub 2013 Mar 4. Review. PubMed PMID: 23458511.

4: Funakoshi T, Latif A, Galsky MD. Risk of hematologic toxicities in cancer patients treated with sunitinib: a systematic review and meta-analysis. Cancer Treat Rev. 2013 Nov;39(7):818-30. doi: 10.1016/j.ctrv.2013.01.004. Epub 2013 Feb 28. Review. PubMed PMID: 23455076.

5: Funakoshi T, Shimada YJ. Risk of hypothyroidism in patients with cancer treated with sunitinib: a systematic review and meta-analysis. Acta Oncol. 2013 May;52(4):691-702. doi: 10.3109/0284186X.2012.752579. Epub 2013 Jan 3. Review. PubMed PMID: 23282114.

6: Gallucci G, Tartarone A, Tocchetti CG, Bochicchio AM, Coccaro M, Capobianco A, Maurea N, Improta G, Zupa A, Aieta M. Role of preeclampsia-related angiogenic factors in sunitinib cardiotoxicity: two cases and review of the literature. Future Oncol. 2013 Jan;9(1):127-33. doi: 10.2217/fon.12.162. Review. PubMed PMID: 23252570.

7: Lele AV, Clutter S, Price E, De Ruyter ML. Severe hypothyroidism presenting as myxedema coma in the postoperative period in a patient taking sunitinib: case report and review of literature. J Clin Anesth. 2013 Feb;25(1):47-51. doi: 10.1016/j.jclinane.2012.07.001. Epub 2012 Dec 16. Review. PubMed PMID: 23246982.

8: Khan KH, Fenton A, Murtagh E, McAleer JJ, Clayton A. Reversible posterior leukoencephalopathy syndrome following sunitinib therapy: a case report and review of the literature. Tumori. 2012 Sep-Oct;98(5):139e-142e. doi: 10.1700/1190.13216. Review. PubMed PMID: 23235770.

9: Erdem L, Giovannetti E, Leon LG, Honeywell R, Peters GJ. Polymorphisms to predict outcome to the tyrosine kinase inhibitors gefitinib, erlotinib, sorafenib and sunitinib. Curr Top Med Chem. 2012;12(15):1649-59. Review. PubMed PMID: 22978339.

10: Sunitinib and pancreatic neuroendocrine tumours. More assessment needed. Prescrire Int. 2012 May;21(127):123-5. Review. PubMed PMID: 22827001.

11: Raymond E, Hammel P, Dreyer C, Maatescu C, Hentic O, Ruszniewski P, Faivre S. Sunitinib in pancreatic neuroendocrine tumors. Target Oncol. 2012 Jun;7(2):117-25. doi: 10.1007/s11523-012-0220-2. Epub 2012 Jun 2. Review. PubMed PMID: 22661319.

12: Castellano D, Ravaud A, Schmidinger M, De Velasco G, Vazquez F. Therapy management with sunitinib in patients with metastatic renal cell carcinoma: key concepts and the impact of clinical biomarkers. Cancer Treat Rev. 2013 May;39(3):230-40. doi: 10.1016/j.ctrv.2012.04.009. Epub 2012 May 28. Review. PubMed PMID: 22647546.

13: Wood L. Sunitinib malate for the treatment of renal cell carcinoma. Expert Opin Pharmacother. 2012 Jun;13(9):1323-36. doi: 10.1517/14656566.2012.689130. Review. PubMed PMID: 22607009.

14: Zhou A. Management of sunitinib adverse events in renal cell carcinoma patients: the Asian experience. Asia Pac J Clin Oncol. 2012 Jun;8(2):132-44. doi: 10.1111/j.1743-7563.2012.01525.x. Review. PubMed PMID: 22524572.

15: Mateo J, Heymach JV, Zurita AJ. Circulating biomarkers of response to sunitinib in gastroenteropancreatic neuroendocrine tumors: current data and clinical outlook. Mol Diagn Ther. 2012 Jun 1;16(3):151-61. doi: 10.2165/11632590-000000000-00000. Review. PubMed PMID: 22515658; PubMed Central PMCID: PMC3872147.

16: Kassem MG, Motiur Rahman AF, Korashy HM. Sunitinib malate. Profiles Drug Subst Excip Relat Methodol. 2012;37:363-88. doi: 10.1016/B978-0-12-397220-0.00009-X. Epub 2012 Mar 19. Review. PubMed PMID: 22469323.

17: Vázquez S, León L, Fernández O, Lázaro M, Grande E, Aparicio L. Sunitinib: the first to arrive at first-line metastatic renal cell carcinoma. Adv Ther. 2012 Mar;29(3):202-17. doi: 10.1007/s12325-011-0099-9. Epub 2012 Feb 7. Review. PubMed PMID: 22328304.

18: Aparicio-Gallego G, Blanco M, Figueroa A, García-Campelo R, Valladares-Ayerbes M, Grande-Pulido E, Antón-Aparicio L. New insights into molecular mechanisms of sunitinib-associated side effects. Mol Cancer Ther. 2011 Dec;10(12):2215-23. doi: 10.1158/1535-7163.MCT-10-1124. Review. PubMed PMID: 22161785.

19: Hubner RA, Valle JW. Sunitinib for advanced pancreatic neuroendocrine tumors. Expert Rev Anticancer Ther. 2011 Dec;11(12):1817-27. doi: 10.1586/era.11.171. Review. PubMed PMID: 22117148.

20: Aparicio LM, Pulido EG, Gallego GA. Sunitinib-induced asthenia: from molecular basis to clinical relief. Cancer Biol Ther. 2011 Nov 1;12(9):765-71. doi: 10.4161/cbt.12.9.18138. Review. PubMed PMID: 22045104. 



Additional Information

Sunitinib malate is the orally bioavailable malate salt of an indolinone-based tyrosine kinase inhibitor with potential antineoplastic activity. Sunitinib blocks the tyrosine kinase activities of vascular endothelial growth factor receptor 2 (VEGFR2), platelet-derived growth factor receptor b (PDGFRb), and c-kit, thereby inhibiting angiogenesis and cell proliferation. This agent also inhibits the phosphorylation of Fms-related tyrosine kinase 3 (FLT3), another receptor tyrosine kinase expressed by some leukemic cells. 
 
Sunitinib malate is a yellow to orange powder with a pKa of 8.95. The solubility of sunitinib malate in aqueous media over the range pH 1.2 to pH 6.8 is in excess of 25 mg/mL. The log of the distribution coefficient (octanol/water) at pH 7 is 5.2. SUTENT (sunitinib malate) capsules are supplied as printed hard shell capsules containing sunitinib malate equivalent to 12.5 mg, 25 mg or 50 mg of sunitinib together with mannitol, croscarmellose sodium, povidone (K-25) and magnesium stearate as inactive  ngredients. The orange gelatin capsule shells contain titanium dioxide, and red iron oxide. The caramel gelatin capsule shells also contain yellow iron oxide and black iron oxide. The printing ink contains shellac, propylene glycol, sodium hydroxide, povidone and titanium dioxide.
 
Sunitinib (marketed as Sutent by Pfizer, and previously known as SU11248) is an oral, small-molecule, multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal tumor (GIST) on January 26, 2006. Sunitinib was the first cancer drug simultaneously approved for two different indications. Sunitinib has become a standard of care for both of these cancers, and is currently being studied for the treatment of many others.
 
 
According to http://en.wikipedia.org/wiki/Sunitinib, Sunitinib is a standard of care in the first-line treatment of metastatic RCC, other therapeutic options in this setting are sorafenib (Nexavar), temsirolimus (Torisel) and interleukin-2 (Proleukin). RCC is generally resistant to chemotherapy or radiation. Prior to RTKs, metastatic disease could only be treated with the cytokines interferon alpha (IFNα) or Interleukin 2 (IL-2). However, these agents demonstrated low rates of efficacy (5%-20%). In two separate Phase II studies, sunitinib demonstrated consistent response rates of approximately 40% in patients who had already failed cytokine therapy. Although these were Phase II studies, these results were impressive enough for the FDA to approve sunitinib for first-line use even before Phase III data were available. The results of the Phase III study, published in the New England Journal of Medicine in 2007, proved that sunitinib offers superior efficacy compared with IFNα. Progression-free survival (primary endpoint) was more than doubled: 11 months for sunitinib compared with 5 months for IFNα (P<.000001). The benefit for sunitinib was significant across all major patient subgroups, including those with a poor prognosis at baseline. Secondary endpoints also favored sunitinib. 28% of sunitinib patients had significant tumor shrinkage (objective response) compared with only 5% of patients who received IFNα (P<.001). Although overall survival data are not yet mature, there is a clear trend toward improved survival with sunitinib. Patients receiving sunitinib also reported a significantly better quality of life than those treated with IFNα (P<.001).
According to http://en.wikipedia.org/wiki/Sunitinib, Sunitinib is a standard of care in the first-line treatment of metastatic RCC, other therapeutic options in this setting are sorafenib (Nexavar), temsirolimus (Torisel) and interleukin-2 (Proleukin). RCC is generally resistant to chemotherapy or radiation. Prior to RTKs, metastatic disease could only be treated with the cytokines interferon alpha (IFNα) or Interleukin 2 (IL-2). However, these agents demonstrated low rates of efficacy (5%-20%). In two separate Phase II studies, sunitinib demonstrated consistent response rates of approximately 40% in patients who had already failed cytokine therapy. Although these were Phase II studies, these results were impressive enough for the FDA to approve sunitinib for first-line use even before Phase III data were available. The results of the Phase III study, published in the New England Journal of Medicine in 2007, proved that sunitinib offers superior efficacy compared with IFNα. Progression-free survival (primary endpoint) was more than doubled: 11 months for sunitinib compared with 5 months for IFNα (P<.000001). The benefit for sunitinib was significant across all major patient subgroups, including those with a poor prognosis at baseline. Secondary endpoints also favored sunitinib. 28% of sunitinib patients had significant tumor shrinkage (objective response) compared with only 5% of patients who received IFNα (P<.001). Although overall survival data are not yet mature, there is a clear trend toward improved survival with sunitinib. Patients receiving sunitinib also reported a significantly better quality of life than those treated with IFNα (P<.001).