WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 200135
CAS#: 1218779-75-9 (mesylate)
Description: Rivoceranib, also known as Apatinib and YN-968D1, is an orally bioavailable, small-molecule receptor tyrosine kinase inhibitor with potential antiangiogenic and antineoplastic activities. The free-base form is also known as Rivoceranib. Apatinib selectively binds to and inhibits vascular endothelial growth factor receptor 2, which may inhibit VEGF-stimulated endothelial cell migration and proliferation and decrease tumor microvessel density. In addition, this agent mildly inhibits c-Kit and c-SRC tyrosine kinases.
MedKoo Cat#: 200135
Name: Apatinib mesylate
CAS#: 1218779-75-9 (mesylate)
Chemical Formula: C25H27N5O4S
Molecular Weight: 493.58
Elemental Analysis: C, 60.83; H, 5.51; N, 14.19; O, 12.97; S, 6.50
Synonym: YN-968D1; YN 968D1; YN968D1; Rivoceranib; Apatinib; Apatinib mesylate.
IUPAC/Chemical Name: N-(4-(1-cyanocyclopentyl)phenyl)-2-((4-methylpyridin-3-yl)amino)nicotinamide methanesulfonate
InChi Key: BDGPIQYIFFSTGI-UHFFFAOYSA-N
InChi Code: InChI=1S/C24H23N5O.CH4O3S/c1-17-10-14-26-15-21(17)29-22-20(5-4-13-27-22)23(30)28-19-8-6-18(7-9-19)24(16-25)11-2-3-12-24;1-5(2,3)4/h4-10,13-15H,2-3,11-12H2,1H3,(H,27,29)(H,28,30);1H3,(H,2,3,4)
SMILES Code: O=C(NC1=CC=C(C2(C#N)CCCC2)C=C1)C3=C(NC4=C(C)C=CN=C4)N=CC=C3.CS(=O)(O)=O
Appearance: 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:||Apatinib mesylate (YN968D1, Rivoceranib) is a potent inhibitor of the VEGF signaling pathway with IC50 values of 1 nM, 13 nM, 429 nM and 530 nM for VEGFR-2, Ret (c-Ret), c-Kit and c-Src, respectively.|
|In vitro activity:||To evaluate the role of Apatinib in osteosarcoma cells, flow cytometry was used to analyze the cells after Annexin V-FITC and propidium iodide (PI) staining. Apatinib-induced apoptosis significantly when compared with the control group (Figure 3a). As a key indicator of apoptosis, the level of cleaved-PARP increased after treatment with Apatinib for 48 h, or with 10 μM Apatinib for different time points (Figure 3d). To determine whether Apatinib inhibited cell proliferation by inducing cell-cycle arrest, the distribution of cell cycle in osteosarcoma cells treated with Apatinib was evaluated. As shown in Figure 3b, accumulation of cells by Apatinib resulted in the G0/G1 phase, whereas a corresponding reduction in both KHOS and MG63 cells in the G2/M and S phases. The expression of cyclin D1 decreased after treatment with Apatinib, as analyzed by western blot (Figure 3d). Terminal deoxynucleotidyl transferase-mediated nick-end labeling staining (TUNEL staining) were used to confirm apoptosis. Treatment with Apatinib increased TUNEL-positive cells when compared with the control (Figure 3c). All the data suggest that Apatinib induces apoptosis and G0/G1-phase arrest. Reference: Cell Death Dis. 2017 Aug 24;8(8):e3015. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596600/|
|In vivo activity:||Apatinib was valid in tumor growth inhibition in vivo. The tumor volume decreased when compared with the control group (Figures 7a and b). In accordance with the in vitro experiment, Figure 7c shows that Apatinib treatment increased the level of LC3-II and Bax, whereas the level of BCL-2 and VEGFR2 decreased in vivo. Immunohistochemistry showed that Apatinib decreased the expression of VEGFR2, p-STAT3 and BCL-2 in tumors formed by KHOS cells (Figure 7d). All the results revealed that Apatinib inhibited the growth of osteosarcoma in vivo. Reference: Cell Death Dis. 2017 Aug 24;8(8):e3015. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596600/|
|Solvent||Max Conc. mg/mL||Max Conc. mM|
The following data is based on the product molecular weight 493.58 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.
|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. Liu K, Ren T, Huang Y, Sun K, Bao X, Wang S, Zheng B, Guo W. Apatinib promotes autophagy and apoptosis through VEGFR2/STAT3/BCL-2 signaling in osteosarcoma. Cell Death Dis. 2017 Aug 24;8(8):e3015. doi: 10.1038/cddis.2017.422. PMID: 28837148; PMCID: PMC5596600. 2. Yang C, Qin S. Apatinib targets both tumor and endothelial cells in hepatocellular carcinoma. Cancer Med. 2018 Sep;7(9):4570-4583. doi: 10.1002/cam4.1664. Epub 2018 Aug 14. PMID: 30109780; PMCID: PMC6144148.|
|In vitro protocol:||1. Liu K, Ren T, Huang Y, Sun K, Bao X, Wang S, Zheng B, Guo W. Apatinib promotes autophagy and apoptosis through VEGFR2/STAT3/BCL-2 signaling in osteosarcoma. Cell Death Dis. 2017 Aug 24;8(8):e3015. doi: 10.1038/cddis.2017.422. PMID: 28837148; PMCID: PMC5596600. 2. Yang C, Qin S. Apatinib targets both tumor and endothelial cells in hepatocellular carcinoma. Cancer Med. 2018 Sep;7(9):4570-4583. doi: 10.1002/cam4.1664. Epub 2018 Aug 14. PMID: 30109780; PMCID: PMC6144148.|
|In vivo protocol:||1. Liu K, Ren T, Huang Y, Sun K, Bao X, Wang S, Zheng B, Guo W. Apatinib promotes autophagy and apoptosis through VEGFR2/STAT3/BCL-2 signaling in osteosarcoma. Cell Death Dis. 2017 Aug 24;8(8):e3015. doi: 10.1038/cddis.2017.422. PMID: 28837148; PMCID: PMC5596600. 2. Yang C, Qin S. Apatinib targets both tumor and endothelial cells in hepatocellular carcinoma. Cancer Med. 2018 Sep;7(9):4570-4583. doi: 10.1002/cam4.1664. Epub 2018 Aug 14. PMID: 30109780; PMCID: PMC6144148.|
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3: Ikeda S, Takano Y, Schwab D, Portron A, Kasahara-Ito N, Saito T, Iida S. Effect of Renal Impairment on the Pharmacokinetics and Pharmacodynamics of Tofogliflozin (A SELECTIVE SGLT2 Inhibitor) in Patients with Type 2 Diabetes Mellitus. Drug Res (Stuttg). 2018 Aug 13. doi: 10.1055/a-0662-0209. [Epub ahead of print] PubMed PMID: 30103216.
4: Sakaeda T, Kobuchi S, Yoshioka R, Haruna M, Takahata N, Ito Y, Sugano A, Fukuzawa K, Hayase T, Hayakawa T, Nakayama H, Takaoka Y, Tohkin M. Susceptibility to serious skin and subcutaneous tissue disorders and skin tissue distribution of sodium-dependent glucose co-transporter type 2 (SGLT2) inhibitors. Int J Med Sci. 2018 Jun 13;15(9):937-943. doi: 10.7150/ijms.22224. eCollection 2018. PubMed PMID: 30008607; PubMed Central PMCID: PMC6036094.
5: Kusunoki M, Natsume Y, Miyata T, Tsutsumi K, Oshida Y. Effects of Concomitant Administration of a Dipeptidyl Peptidase-4 Inhibitor in Japanese Patients with Type 2 Diabetes Showing Relatively Good Glycemic Control Under Treatment with a Sodium Glucose Co-Transporter 2 Inhibitor. Drug Res (Stuttg). 2018 Jul 2. doi: 10.1055/a-0585-0145. [Epub ahead of print] PubMed PMID: 29966149.
6: Bekki M, Tahara N, Tahara A, Igata S, Honda A, Sugiyama Y, Nakamura T, Sun J, Kumashiro Y, Matsui T, Fukumoto Y, Yamagishi S-I. Switching dipeptidyl peptidase-4 inhibitors to tofogliflozin, a selective inhibitor of sodium-glucose cotransporter 2 improves arterial stiffness evaluated by cardio-ankle vascular index in patients with type 2 diabetes: a pilot study. Curr Vasc Pharmacol. 2018 May 15. doi: 10.2174/1570161116666180515154555. [Epub ahead of print] PubMed PMID: 29766812.
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8: Kahathuduwa CN, Thomas DM, Siu C, Allison DB. Unaccounted for regression to the mean renders conclusion of article titled "Uric acid lowering in relation to HbA1c reductions with the SGLT2 inhibitor tofogliflozin" unsubstantiated. Diabetes Obes Metab. 2018 Aug;20(8):2039-2040. doi: 10.1111/dom.13323. Epub 2018 May 3. PubMed PMID: 29660244; PubMed Central PMCID: PMC6043394.
9: Kosiborod M, Lam CSP, Kohsaka S, Kim DJ, Karasik A, Shaw J, Tangri N, Goh SY, Thuresson M, Chen H, Surmont F, Hammar N, Fenici P; CVD-REAL Investigators and Study Group. Cardiovascular Events Associated With SGLT-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL 2 Study. J Am Coll Cardiol. 2018 Jun 12;71(23):2628-2639. doi: 10.1016/j.jacc.2018.03.009. Epub 2018 Mar 11. PubMed PMID: 29540325.
10: Ito S, Hosaka T, Yano W, Itou T, Yasumura M, Shimizu Y, Kobayashi H, Nakagawa T, Inoue K, Tanabe S, Kondo T, Ishida H. Metabolic effects of Tofogliflozin are efficiently enhanced with appropriate dietary carbohydrate ratio and are distinct from carbohydrate restriction. Physiol Rep. 2018 Mar;6(5). doi: 10.14814/phy2.13642. PubMed PMID: 29520981; PubMed Central PMCID: PMC5843757.
11: Kamei S, Iwamoto M, Kameyama M, Shimoda M, Kinoshita T, Obata A, Kimura T, Hirukawa H, Tatsumi F, Kohara K, Nakanishi S, Mune T, Kaku K, Kaneto H. Effect of Tofogliflozin on Body Composition and Glycemic Control in Japanese Subjects with Type 2 Diabetes Mellitus. J Diabetes Res. 2018 Jan 8;2018:6470137. doi: 10.1155/2018/6470137. eCollection 2018. PubMed PMID: 29507863; PubMed Central PMCID: PMC5817268.
12: Horikawa Y, Enya M, Komagata M, Hashimoto KI, Kagami M, Fukami M, Takeda J. Effectiveness of Sodium-Glucose Cotransporter-2 Inhibitor as an Add-on Drug to GLP-1 Receptor Agonists for Glycemic Control of a Patient with Prader-Willi Syndrome: A Case Report. Diabetes Ther. 2018 Feb;9(1):421-426. doi: 10.1007/s13300-018-0369-5. Epub 2018 Jan 15. PubMed PMID: 29335890; PubMed Central PMCID: PMC5801255.
13: Terauchi Y, Tamura M, Senda M, Gunji R, Kaku K. Long-term safety and efficacy of tofogliflozin as add-on to insulin in patients with type 2 diabetes: Results from a 52-week, multicentre, randomized, double-blind, open-label extension, Phase 4 study in Japan (J-STEP/INS). Diabetes Obes Metab. 2018 May;20(5):1176-1185. doi: 10.1111/dom.13213. Epub 2018 Feb 11. PubMed PMID: 29316236; PubMed Central PMCID: PMC5947124.
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16: Cai X, Yang W, Gao X, Chen Y, Zhou L, Zhang S, Han X, Ji L. The Association Between the Dosage of SGLT2 Inhibitor and Weight Reduction in Type 2 Diabetes Patients: A Meta-Analysis. Obesity (Silver Spring). 2018 Jan;26(1):70-80. doi: 10.1002/oby.22066. Epub 2017 Nov 22. PubMed PMID: 29165885.
17: Tobe K, Suganami H, Kaku K. Sodium-glucose cotransporter 2 inhibitor, tofogliflozin, shows better improvements of blood glucose and insulin secretion in patients with high insulin levels at baseline. J Diabetes Investig. 2018 Jul;9(4):862-869. doi: 10.1111/jdi.12761. Epub 2017 Nov 13. PubMed PMID: 29032638; PubMed Central PMCID: PMC6031493.
18: Obara K, Shirakami Y, Maruta A, Ideta T, Miyazaki T, Kochi T, Sakai H, Tanaka T, Seishima M, Shimizu M. Preventive effects of the sodium glucose cotransporter 2 inhibitor tofogliflozin on diethylnitrosamine-induced liver tumorigenesis in obese and diabetic mice. Oncotarget. 2017 Apr 6;8(35):58353-58363. doi: 10.18632/oncotarget.16874. eCollection 2017 Aug 29. PubMed PMID: 28938561; PubMed Central PMCID: PMC5601657.
19: Sawada Y, Izumida Y, Takeuchi Y, Aita Y, Wada N, Li E, Murayama Y, Piao X, Shikama A, Masuda Y, Nishi-Tatsumi M, Kubota M, Sekiya M, Matsuzaka T, Nakagawa Y, Sugano Y, Iwasaki H, Kobayashi K, Yatoh S, Suzuki H, Yagyu H, Kawakami Y, Kadowaki T, Shimano H, Yahagi N. Effect of sodium-glucose cotransporter 2 (SGLT2) inhibition on weight loss is partly mediated by liver-brain-adipose neurocircuitry. Biochem Biophys Res Commun. 2017 Nov 4;493(1):40-45. doi: 10.1016/j.bbrc.2017.09.081. Epub 2017 Sep 18. PubMed PMID: 28928093.
20: Katakami N, Mita T, Yoshii H, Shiraiwa T, Yasuda T, Okada Y, Umayahara Y, Kaneto H, Osonoi T, Yamamoto T, Kuribayashi N, Maeda K, Yokoyama H, Kosugi K, Ohtoshi K, Hayashi I, Sumitani S, Tsugawa M, Ohashi M, Taki H, Nakamura T, Kawashima S, Sato Y, Watada H, Shimomura I; UTOPIA study investigators. Rationale, Design, and Baseline Characteristics of the Utopia Trial for Preventing Diabetic Atherosclerosis Using an SGLT2 Inhibitor: A Prospective, Randomized, Open-Label, Parallel-Group Comparative Study. Diabetes Ther. 2017 Oct;8(5):999-1013. doi: 10.1007/s13300-017-0292-1. Epub 2017 Sep 1. PubMed PMID: 28864997; PubMed Central PMCID: PMC5630549.
1218779-75-9 (Apatinib mesylate salt)
811803-05-1 (Apatinib free base).
Apatinib, also known as YN968D1, is a tyrosine kinase inhibitor that selectively inhibits the vascular endothelial growth factor receptor-2 (VEGFR2, also known as KDR). It is an orally bioavailable, small molecule agent which is thought to inhibit angiogenesis in cancer cells; specifically apatinib inhibits VEGF-mediated endothelial cell migration and proliferation thus blocking new blood vessel formation in tumor tissue. This agent also mildly inhibits c-Kit and c-SRC tyrosine kinases.
History of Apatinib: Apatinib was first synthesized by Advenchen Laboratories in California, USA and is being developed by Jiangsu Hengrui Medicine (China), LSK BioPartners (US) and Bukwang Pharmaceutical Company (Korea). It is an investigational cancer drug currently undergoing clinical trials as a potential targeted treatment for metastatic gastric carcinoma, metastatic breast cancer and advanced hepatocellular carcinoma. (source: http://en.wikipedia.org/wiki/Apatinib).
Development status of Apatinib: There is a Phase II/III study recruiting patients in China to determine whether apatinib can improve progression free survival compared with placebo in patients with metastatic gastric carcinoma who have failed two lines of chemotherapy (September, 2009). As of November, 2010, two additional Phase 2 clinical studies have been initiated for apatinib in metastatic triple-negative breast cancer patients and advanced hepatocellular carcinoma. On March 7, 2011, Bukwang announced that it filed an IND to the Korean FDA to begin Human clinical studies of Apatinib in Phase 2. (source: http://en.wikipedia.org/wiki/Apatinib).