Brivanib
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MedKoo CAT#: 200569

CAS#: 649735-46-6

Description: Brivanib is the hydrolyzed form of Brivanib alaninate, which is a vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor with potential antineoplastic activity. Brivanib strongly binds to and inhibits VEGFR2, a tyrosine kinase receptor expressed almost exclusively on vascular endothelial cells; inhibition of VEGFR2 may result in inhibition of tumor angiogenesis, inhibition of tumor cell growth, and tumor regression.

Chemical Structure

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Brivanib
CAS# 649735-46-6
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 200569
Name: Brivanib
CAS#: 649735-46-6
Chemical Formula: C19H19FN4O3
Exact Mass: 370.14
Molecular Weight: 370.378
Elemental Analysis: C, 61.61; H, 5.17; F, 5.13; N, 15.13; O, 12.96

Price and Availability

Size Price Availability Quantity
10mg USD 250 2 Weeks
25mg USD 450 2 Weeks
50mg USD 800 2 Weeks
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Related CAS #: 649735-46-6   649735-63-7 (alaninate)    

Synonym: BMS540215; BMS-540215; BMS 540215.

IUPAC/Chemical Name: (R)-1-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl)oxy)propan-2-ol

InChi Key: WCWUXEGQKLTGDX-LLVKDONJSA-N

InChi Code: InChI=1S/C19H19FN4O3/c1-10-6-13-14(23-10)4-5-15(17(13)20)27-19-18-12(3)16(26-8-11(2)25)7-24(18)22-9-21-19/h4-7,9,11,23,25H,8H2,1-3H3/t11-/m1/s1

SMILES Code: C[C@@H](O)COC1=CN2N=CN=C(OC3=C(F)C4=C(NC(C)=C4)C=C3)C2=C1C

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 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

More Info: Brivanib has a favorable cytochrome P450 profile and a low potential for drug-drug interactions. It inhibits growth of various solid carcinomas including hepatocellular carcinoma (HCC) xenografts in vivo. Brivanib-induced growth inhibition is associated with inhibition of angiogenesis and cell proliferation, and increased apoptosis. In phase I studies in patients with advanced or metastatic solid tumors, brivanib was well tolerated and had antitumor activity. In the phase II, open-label study, brivanib demonstrated promising efficacy and tolerability in patients with unresectable locally advanced or metastatic HCC as both first- and second-line treatment after exposure to prior therapy, including other antiangiogenics. As a result of these data, brivanib is in phase III development in HCC and in combination with other agents for treatment of various tumors, including colorectal cancer. [ source: Huynh, H., Fargnoli, J. Brivanib alaninate, Drugs of the Future, 2009, 34(11): 88 1)   Phase II study of Brivanib. Between March 2007 and May 2009, 55 patients were treated and were evaluable for response. Patients were assessed using modified World Health Organization (mWHO) criteria. According to mWHO criteria and as assessed by Independent Response Review Committee, the six-month progression-free survival rate (95% CI) was 18.2% (9.1%-30.9%). Median progression-free survival (95% CI) was 2.7 months (1.4-3.0). One patient achieved a complete response and three achieved a partial response. Twenty-two had stable disease. Median overall survival (95% CI) was 10 (6.8-15.2) months. Brivanib was generally well tolerated; the most common adverse events included fatigue, hypertension, and diarrhea. Brivanib as first-line therapy demonstrates promising antitumor activity and a manageable safety profile in patients with advanced, unresectable HCC. (source: Clin Cancer Res. 2011 Apr 1;17(7):1973-83).   

Product Data:
Product Data
Instruction:
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Biological target: Brivanib (BMS-540215) is an ATP-competitive inhibitor against VEGFR2 with an IC50 of 25 nM, and has moderate potency against VEGFR-1 and FGFR-1, but >240-fold against PDGFR-β.
In vitro activity: In vitro cell experiments demonstrated that brivanib inhibited the proliferation, migration and tube formation of microvascular endothelial cells. Reference: J Cell Physiol. 2020 Feb;235(2):1259-1273. https://pubmed.ncbi.nlm.nih.gov/31270802/
In vivo activity: After in vivo induction with BDL, CCl4, and TAA, mice treated with brivanib showed reduced liver fibrosis and decreased expression of collagen Iα1 and α-smooth muscle actin in the liver. Reference: PLoS One. 2014 Apr 7;9(4):e92273. https://pubmed.ncbi.nlm.nih.gov/24710173/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 41.5 112.05
DMSO:PBS (pH 7.2) (1:4) 0.2 0.54
DMF 33.0 89.10
Ethanol 3.0 8.10

Preparing Stock Solutions

The following data is based on the product molecular weight 370.38 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 L, Zhu M, Wu W, Qin B, Gu J, Tu Y, Chen J, Liu D, Shi Y, Liu X, Sang A, Ding D. Brivanib, a multitargeted small-molecule tyrosine kinase inhibitor, suppresses laser-induced CNV in a mouse model of neovascular AMD. J Cell Physiol. 2020 Feb;235(2):1259-1273. doi: 10.1002/jcp.29041. Epub 2019 Jul 4. PMID: 31270802. 2. Nakamura I, Zakharia K, Banini BA, Mikhail DS, Kim TH, Yang JD, Moser CD, Shaleh HM, Thornburgh SR, Walters I, Roberts LR. Brivanib attenuates hepatic fibrosis in vivo and stellate cell activation in vitro by inhibition of FGF, VEGF and PDGF signaling. PLoS One. 2014 Apr 7;9(4):e92273. doi: 10.1371/journal.pone.0092273. Erratum in: PLoS One. 2015;10(11):e0142355. PMID: 24710173; PMCID: PMC3977817.
In vitro protocol: 1. Li L, Zhu M, Wu W, Qin B, Gu J, Tu Y, Chen J, Liu D, Shi Y, Liu X, Sang A, Ding D. Brivanib, a multitargeted small-molecule tyrosine kinase inhibitor, suppresses laser-induced CNV in a mouse model of neovascular AMD. J Cell Physiol. 2020 Feb;235(2):1259-1273. doi: 10.1002/jcp.29041. Epub 2019 Jul 4. PMID: 31270802. 2. Nakamura I, Zakharia K, Banini BA, Mikhail DS, Kim TH, Yang JD, Moser CD, Shaleh HM, Thornburgh SR, Walters I, Roberts LR. Brivanib attenuates hepatic fibrosis in vivo and stellate cell activation in vitro by inhibition of FGF, VEGF and PDGF signaling. PLoS One. 2014 Apr 7;9(4):e92273. doi: 10.1371/journal.pone.0092273. Erratum in: PLoS One. 2015;10(11):e0142355. PMID: 24710173; PMCID: PMC3977817.
In vivo protocol: 1. Li L, Zhu M, Wu W, Qin B, Gu J, Tu Y, Chen J, Liu D, Shi Y, Liu X, Sang A, Ding D. Brivanib, a multitargeted small-molecule tyrosine kinase inhibitor, suppresses laser-induced CNV in a mouse model of neovascular AMD. J Cell Physiol. 2020 Feb;235(2):1259-1273. doi: 10.1002/jcp.29041. Epub 2019 Jul 4. PMID: 31270802. 2. Nakamura I, Zakharia K, Banini BA, Mikhail DS, Kim TH, Yang JD, Moser CD, Shaleh HM, Thornburgh SR, Walters I, Roberts LR. Brivanib attenuates hepatic fibrosis in vivo and stellate cell activation in vitro by inhibition of FGF, VEGF and PDGF signaling. PLoS One. 2014 Apr 7;9(4):e92273. doi: 10.1371/journal.pone.0092273. Erratum in: PLoS One. 2015;10(11):e0142355. PMID: 24710173; PMCID: PMC3977817.

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1: Diaz-Padilla I, Siu LL. Brivanib alaninate for cancer. Expert Opin Investig Drugs. 2011 Apr;20(4):577-86. doi: 10.1517/13543784.2011.565329. Epub 2011 Mar 11. PMID: 21391890.


2: Chou T, Finn RS. Brivanib: a review of development. Future Oncol. 2012 Sep;8(9):1083-90. doi: 10.2217/fon.12.104. PMID: 23030483.


3: Wan Y, Wu W, Wan Y, Li L, Zhang J, Chen X, Liu S, Yao X. Brivanib alaninate inhibited dengue virus proliferation through VEGFR2/AMPK pathway. Pharmacol Res. 2021 Aug;170:105721. doi: 10.1016/j.phrs.2021.105721. Epub 2021 Jun 8. PMID: 34116207.


4: Dempke WC, Zippel R. Brivanib, a novel dual VEGF-R2/bFGF-R inhibitor. Anticancer Res. 2010 Nov;30(11):4477-83. PMID: 21115896.


5: Li L, Zhu M, Wu W, Qin B, Gu J, Tu Y, Chen J, Liu D, Shi Y, Liu X, Sang A, Ding D. Brivanib, a multitargeted small-molecule tyrosine kinase inhibitor, suppresses laser-induced CNV in a mouse model of neovascular AMD. J Cell Physiol. 2020 Feb;235(2):1259-1273. doi: 10.1002/jcp.29041. Epub 2019 Jul 4. PMID: 31270802.


6: Kelley RK. Brivanib and FOLFOX in hepatocellular carcinoma: finding the common themes among negative trials. J Clin Oncol. 2013 Oct 1;31(28):3483-6. doi: 10.1200/JCO.2013.49.7941. Epub 2013 Aug 26. PMID: 23980088.


7: Giovannini C, Salzano AM, Baglioni M, Vitale M, Scaloni A, Zambrano N, Giannone FA, Vasuri F, D'Errico A, Svegliati Baroni G, Bolondi L, Gramantieri L. Brivanib in combination with Notch3 silencing shows potent activity in tumour models. Br J Cancer. 2019 Mar;120(6):601-611. doi: 10.1038/s41416-018-0375-4. Epub 2019 Feb 15. PMID: 30765875; PMCID: PMC6461893.


8: Hofman J, Sorf A, Vagiannis D, Sucha S, Kammerer S, Küpper JH, Chen S, Guo L, Ceckova M, Staud F. Brivanib Exhibits Potential for Pharmacokinetic Drug-Drug Interactions and the Modulation of Multidrug Resistance through the Inhibition of Human ABCG2 Drug Efflux Transporter and CYP450 Biotransformation Enzymes. Mol Pharm. 2019 Nov 4;16(11):4436-4450. doi: 10.1021/acs.molpharmaceut.9b00361. Epub 2019 Oct 21. PMID: 31633365.


9: Llovet JM, Decaens T, Raoul JL, Boucher E, Kudo M, Chang C, Kang YK, Assenat E, Lim HY, Boige V, Mathurin P, Fartoux L, Lin DY, Bruix J, Poon RT, Sherman M, Blanc JF, Finn RS, Tak WY, Chao Y, Ezzeddine R, Liu D, Walters I, Park JW. Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS study. J Clin Oncol. 2013 Oct 1;31(28):3509-16. doi: 10.1200/JCO.2012.47.3009. Epub 2013 Aug 26. PMID: 23980090.


10: Nakamura I, Zakharia K, Banini BA, Mikhail DS, Kim TH, Yang JD, Moser CD, Shaleh HM, Thornburgh SR, Walters I, Roberts LR. Brivanib attenuates hepatic fibrosis in vivo and stellate cell activation in vitro by inhibition of FGF, VEGF and PDGF signaling. PLoS One. 2014 Apr 7;9(4):e92273. doi: 10.1371/journal.pone.0092273. Erratum in: PLoS One. 2015;10(11):e0142355. PMID: 24710173; PMCID: PMC3977817.


11: Kudo M. Future treatment option for hepatocellular carcinoma: a focus on brivanib. Dig Dis. 2011;29(3):316-20. doi: 10.1159/000327568. Epub 2011 Aug 9. PMID: 21829023.


12: Allen E, Walters IB, Hanahan D. Brivanib, a dual FGF/VEGF inhibitor, is active both first and second line against mouse pancreatic neuroendocrine tumors developing adaptive/evasive resistance to VEGF inhibition. Clin Cancer Res. 2011 Aug 15;17(16):5299-310. doi: 10.1158/1078-0432.CCR-10-2847. Epub 2011 May 27. PMID: 21622725; PMCID: PMC3156934.


13: Kudo M, Han G, Finn RS, Poon RT, Blanc JF, Yan L, Yang J, Lu L, Tak WY, Yu X, Lee JH, Lin SM, Wu C, Tanwandee T, Shao G, Walters IB, Dela Cruz C, Poulart V, Wang JH. Brivanib as adjuvant therapy to transarterial chemoembolization in patients with hepatocellular carcinoma: A randomized phase III trial. Hepatology. 2014 Nov;60(5):1697-707. doi: 10.1002/hep.27290. Epub 2014 Sep 29. PMID: 24996197.


14: Gong J, Gan J, Masson E, Syed S, Xia YQ, Williams D, Pursley J, Jemal M, Humphreys WG, Iyer RA. Metabolic chiral inversion of brivanib and its relevance to safety and pharmacology. Drug Metab Dispos. 2012 Dec;40(12):2374-80. doi: 10.1124/dmd.112.047340. Epub 2012 Sep 14. PMID: 22983304.


15: Jones RL, Ratain MJ, O'Dwyer PJ, Siu LL, Jassem J, Medioni J, DeJonge M, Rudin C, Sawyer M, Khayat D, Awada A, de Vos-Geelen JMPGM, Evans TRJ, Obel J, Brockstein B, DeGreve J, Baurain JF, Maki R, D'Adamo D, Dickson M, Undevia S, Geary D, Janisch L, Bedard PL, Abdul Razak AR, Kristeleit R, Vitfell-Rasmussen J, Walters I, Kaye SB, Schwartz G. Phase II randomised discontinuation trial of brivanib in patients with advanced solid tumours. Eur J Cancer. 2019 Oct;120:132-139. doi: 10.1016/j.ejca.2019.07.024. Epub 2019 Sep 12. PMID: 31522033; PMCID: PMC8852771.


16: Johnson PJ, Qin S, Park JW, Poon RT, Raoul JL, Philip PA, Hsu CH, Hu TH, Heo J, Xu J, Lu L, Chao Y, Boucher E, Han KH, Paik SW, Robles-Aviña J, Kudo M, Yan L, Sobhonslidsuk A, Komov D, Decaens T, Tak WY, Jeng LB, Liu D, Ezzeddine R, Walters I, Cheng AL. Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study. J Clin Oncol. 2013 Oct 1;31(28):3517-24. doi: 10.1200/JCO.2012.48.4410. Epub 2013 Aug 26. PMID: 23980084.


17: Huynh H, Ngo VC, Fargnoli J, Ayers M, Soo KC, Koong HN, Thng CH, Ong HS, Chung A, Chow P, Pollock P, Byron S, Tran E. Brivanib alaninate, a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor tyrosine kinases, induces growth inhibition in mouse models of human hepatocellular carcinoma. Clin Cancer Res. 2008 Oct 1;14(19):6146-53. doi: 10.1158/1078-0432.CCR-08-0509. PMID: 18829493.


18: Syed S, Clemens PL, Lathers D, Kollia G, Dhar A, Walters I, Masson E. Lack of effect of brivanib on the pharmacokinetics of midazolam, a CYP3A4 substrate, administered intravenously and orally in healthy participants. J Clin Pharmacol. 2012 Jun;52(6):914-21. doi: 10.1177/0091270011407495. Epub 2011 Jun 9. PMID: 21659627.


19: Gong J, Gan J, Iyer RA. Identification of the oxidative and conjugative enzymes involved in the biotransformation of brivanib. Drug Metab Dispos. 2012 Jan;40(1):219-26. doi: 10.1124/dmd.111.042457. Epub 2011 Oct 11. PMID: 21989950.


20: Mekhail T, Masson E, Fischer BS, Gong J, Iyer R, Gan J, Pursley J, Patricia D, Williams D, Ganapathi R. Metabolism, excretion, and pharmacokinetics of oral brivanib in patients with advanced or metastatic solid tumors. Drug Metab Dispos. 2010 Nov;38(11):1962-6. doi: 10.1124/dmd.110.033951. Epub 2010 Jul 29. PMID: 20671097; PMCID: PMC2967392.