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Brivanib Alaninate (BMS-582664)

VEGFR2 inhibitor,ATP-competitive CAS# 649735-63-7

Brivanib Alaninate (BMS-582664)

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Chemical structure

Brivanib Alaninate (BMS-582664)

3D structure

Chemical Properties of Brivanib Alaninate (BMS-582664)

Cas No. 649735-63-7 SDF Download SDF
PubChem ID 11154925 Appearance Powder
Formula C22H24FN5O4 M.Wt 441.46
Type of Compound N/A Storage Desiccate at -20°C
Synonyms BMS-582664
Solubility DMSO : ≥ 100 mg/mL (226.52 mM)
*"≥" means soluble, but saturation unknown.
Chemical Name [(2R)-1-[4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]oxypropan-2-yl] (2S)-2-aminopropanoate
SMILES CC1=CC2=C(N1)C=CC(=C2F)OC3=NC=NN4C3=C(C(=C4)OCC(C)OC(=O)C(C)N)C
Standard InChIKey LTEJRLHKIYCEOX-OCCSQVGLSA-N
Standard InChI InChI=1S/C22H24FN5O4/c1-11-7-15-16(27-11)5-6-17(19(15)23)32-21-20-13(3)18(8-28(20)26-10-25-21)30-9-12(2)31-22(29)14(4)24/h5-8,10,12,14,27H,9,24H2,1-4H3/t12-,14+/m1/s1
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of Brivanib Alaninate (BMS-582664)

DescriptionBrivanib Alaninate is an ATP-competitive inhibitor of VEGFR2 with IC50 value of 25 nM.
TargetsVEGFR2    
IC5025 nM     

Protocol

Cell Assay [3]
Viability is measured in LX-2 cells using the Cell Counting Kit-8 (CCK-8). Using 96-well plates with 2,000 cells per well, HSCs are incubated in 10% FBS-supplemented DMEM for 24 hours, followed by starvation in serum-free media. After 24 hours of starvation, brivanib is added at different doses. Two hours later, 5 ng/mL PDGF-BB is added. The cells are incubated for an additional 72 hours and cell viability is measured. Each experiment is performed in three replicates at least four times[3].

Animal Administration [3]
Male mice 4-6 weeks of age are treated 3 times a week with a total of 12 intraperitoneal (i.p.) injections of 150 mL/kg TAA. At the onset of TAA treatment, placebo or brivanib (25 or 50 mg/kg) is administered orally on 5 consecutive days with weekend breaks. The animals are sacrificed 4 weeks after the start of the injections[3].

References:
[1]. Bhide RS, et al. Discovery and preclinical studies of (R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5- methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan- 2-ol (BMS-540215), an in vivo active potent VEGFR-2 inhibitor. J Med Chem, 2006, 49 (7), 2143-2146. [2]. Huynh H, et al. 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, 14(19), 6146-6153. [3]. Nakamura I, et al. Correction: Brivanib Attenuates Hepatic Fibrosis In Vivo and Stellate Cell Activation In Vitro by Inhibition of FGF, VEGF and PDGF Signaling. PLoS One. 2015 Nov 3;10(11):e0142355.

Brivanib Alaninate (BMS-582664) Dilution Calculator

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Preparing Stock Solutions of Brivanib Alaninate (BMS-582664)

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.2652 mL 11.3261 mL 22.6521 mL 45.3042 mL 56.6303 mL
5 mM 0.453 mL 2.2652 mL 4.5304 mL 9.0608 mL 11.3261 mL
10 mM 0.2265 mL 1.1326 mL 2.2652 mL 4.5304 mL 5.663 mL
50 mM 0.0453 mL 0.2265 mL 0.453 mL 0.9061 mL 1.1326 mL
100 mM 0.0227 mL 0.1133 mL 0.2265 mL 0.453 mL 0.5663 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on Brivanib Alaninate (BMS-582664)

BMS-540215 is an ATP-competitive inhibitor of human VEGFR -2, with an IC50 of 25 nmol/L and Ki of 26 nmol/L. In addition, it inhibits VEGFR-1 (IC50 = 380 nmol/L) and VEGFR-3 (IC50 = 10 nmol/L). BMS-540215 also showed good selectivity for FGFR-1 (IC50 = 148 nmol/L), FGFR-2 (IC50 =125 nmol/L), and FGFR-3 (IC50 = 68 nmol/L).
Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) are known to be involved in growth and neovascularization of HCC. Therefore, agents that target these pathways may be effective in the treatment of HCC. Brivanib alaninate is a dual inhibitor ofVEGF receptor (VEGFR) and FGF receptor (FGFR) signaling pathways. Brivanib is hydrolyzed to the active moiety BMS-540215 in vivo.
In vitro: InVEGF-stimulated and basic FGF stimulated SK-HEP1 cells, brivanib significantly inhibited VEGFR-2, FGFR-1, extracellular signal-regulated kinase 1/2, and Akt phosphorylation [1].
In vivo: Six different s.c. patient-derived HCC xenografts were implanted into mice. Tumor growth was evaluated in mice treated with brivanib compared with control. Brivanib significantly suppressed tumor growth in five of six xenograft lines. Tumor weights in these mice that were treated with 50 and 100 mg/kg brivanib by gavage daily for 12 days were approximately 55% and 13%, respectively, compared with vehicle-treated mice. Furthermore, brivanib, at a dose of 100 mg/kg, also inhibited tumor growth in mice with patientderived xenograft lines 2-1318 and 26-1004 [1].
Clinical trial: A total of 750 patients were randomly assigned (376 in arm A and 374 in arm B). Median OS in the intent-to-treat population was 8.8 months in arm A and 8.1 months in arm B. Median progression-free survival (PFS) was 5.0 months in arm A and 3.4 months in arm B. Partial responses observed (13.6% v 7.2%) were higher in arm A. Despite positive effects on PFS and objective response, cetuximab plus brivanib increased toxicity and did not significantly improve OS in patients with metastatic, chemotherapy-refractory, wild-type K-RAS colorectal cancer.
References:
[1] 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;14(19):6146-53.
[2] Siu LL, Shapiro JD, Jonker DJ, Karapetis CS, Zalcberg JR, Simes J, Couture F, Moore MJ, Price TJ, Siddiqui J, Nott LM, Charpentier D, Liauw W, Sawyer MB, Jefford M, Magoski NM, Haydon A, Walters I, Ringash J, Tu D, O'Callaghan CJ. Phase III randomized, placebo-controlled study of cetuximab plus brivanib alaninate versus cetuximab plus placebo in patients with metastatic, chemotherapy-refractory, wild-type K-RAS colorectal carcinoma: the NCIC Clinical Trials Group and AGITG CO.20 Trial. J Clin Oncol. 2013;31(19):2477-84.

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References on Brivanib Alaninate (BMS-582664)

A phase II evaluation of brivanib in the treatment of persistent or recurrent carcinoma of the cervix: An NRG Oncology/Gynecologic Oncology Group study.[Pubmed:28728751]

Gynecol Oncol. 2017 Sep;146(3):554-559.

BACKGROUND: Brivanib is an oral, tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) and fibroblast growth factor receptor (FGFR). We studied its efficacy and tolerability in persistent or recurrent cervical cancer patients. METHODS: Eligible patients had at least one prior cytotoxic regimen for recurrence and with measurable disease. Brivanib 800mg was administered orally every day (1cycle=28days) until disease progression or prohibitive toxicity. Primary endpoints were progression-free survival (PFS) >6months and objective tumor response. RESULTS: Of 28 eligible and evaluable women enrolled, 11 (39%) had primary surgery and 25 (89%) had prior radiation. Eighteen (64%) received one prior cytotoxic treatment and 10 (36%) had 2 prior regimens. Twelve (43%) had >2cycles of brivanib with 4 (14%) receiving >10cycles (range: 1-20). Seven (25%) patients had PFS >6months (90% CI: 7.3%-33.9%). Two (7%) (90% CI: 1.3%-20.8%) patients had partial tumor response with duration of 8 and 22months and 12 (43%) had stable disease. The median PFS was 3.2months (90% CI: 2.1-4.4). The median overall survival was 7.9months (90% CI: 6.1-11.7). More common grade 3 adverse events were hypertension, anemia, hyponatremia, hyperglycemia, elevated liver enzymes, nausea, headache, and colon hemorrhage. Grade 4 adverse events included sepsis and hypertension. CONCLUSIONS: Based on early results of this phase II trial, brivanib was well tolerated and demonstrated sufficient activity after first stage but trial was stopped due to lack of drug availability.

Issues in Managing Hurthle Cell Carcinoma of Thyroid: A Case Report.[Pubmed:28507839]

Cureus. 2017 Apr 14;9(4):e1167.

A 61-year-old woman noticed a right neck lump in October 2001. Fine needle aspiration showed follicular neoplasm, adenoma versus carcinoma. The ultrasound scan showed a solid mass of maximum dimension of 3.7 cm. She had a right thyroid lobectomy and isthmectomy in January 2002 (first surgery). The tissue specimen showed a 4.5 cm Hurthle cell carcinoma (HCC) with vascular invasion. There were no capsular invasion, extra-thyroidal extension, or margin involvement. A completion left lobectomy (second surgery) was performed two weeks later. Therefore the pathological stage is II (T3N0M0). She received adjuvant radioactive iodine ablation for residual thyroid tissue. By 2003, she developed local recurrence, which was resected (third surgery), followed by adjuvant external beam radiotherapy. Unfortunately, she developed further recurrence in the left main bronchus, as identified by Indium-111 Octreotide (Curium, Missouri, USA) and positron emission tomography-computed tomography PET-CT imaging in 2006. She underwent a left pneumonectomy (fourth surgery) in July 2006. In November 2007 she was found to have mediastinal recurrence which was treated with high-dose external beam radiotherapy. She initially responded but developed more local recurrence and a lung metastasis by 2011. She was treated with brivanib with ixabepilone, under a phase I clinical trial with mixed response. Her treatment was discontinued secondary to toxicity and she succumbed to her disease in 2012. This case report illustrates the natural history and clinical decision making for patients diagnosed with HCC of the thyroid. Specifically, we highlight the clinical issues surrounding the histopathological diagnosis, extent of surgical resection, radioiodine diagnostic imaging/ablative treatment, as well as external beam radiotherapy.

An in-depth review of chemical angiogenesis inhibitors for treating hepatocellular carcinoma.[Pubmed:28893090]

Expert Opin Pharmacother. 2017 Oct;18(14):1467-1476.

INTRODUCTION: Hepatocellular carcinoma (HCC) is a frequent and severe complication of cirrhosis. Most HCC patients initially present with or progress to advanced stage disease and require systemic treatment. As hypervascularization is a major characteristic of HCC, antiangiogenic drugs have been tested. Areas covered: In this review, we summarize data on the use of drugs targeting the angiogenesis. Despite many trials, in 2017 only 3 drugs, all antiangiogenic, have demonstrated efficacy in first (sorafenib, lenvatinib) or second line (regorafenib) treatment of advanced HCC. The heterogeneous mechanisms of action and the major reasons for failure of most trials are discussed. An English-language, abstract-based literature review was performed by a PubMed-based strategy. Expert opinion: Currently all trials based on purely antiangiogenic compounds (bevacizumab, linifanib, brivanib and ramucirumab) or drugs with strong antiangiogenic properties (sunitinib) have failed (increased toxicity, minor efficacy and/or flaws in trial design); sorafenib, lenvatinib and regorafenib are multityrosine kinase inhibitors and their efficacy can be partly related to another mechanism of action. We need to better refine future trials design (randomized phase 2, good stratification factors and marker-enriched patient selection) in order to progress toward customized treatment, perhaps in association with immunotherapy.

Objective response by mRECIST as a predictor and potential surrogate end-point of overall survival in advanced HCC.[Pubmed:28131794]

J Hepatol. 2017 Jun;66(6):1166-1172.

BACKGROUND & AIMS: The Modified Response Evaluation Criteria in Solid Tumors (mRECIST) was developed to overcome the limitations of standard RECIST criteria in response assessment of hepatocellular carcinoma (HCC). We aimed to investigate whether objective response by mRECIST accurately predicted overall survival (OS) in patients with advanced HCC treated with systemic targeted therapies and also to preliminarily assess this end-point as a potential surrogate of OS. METHODS: Individual patient data from the BRISK-PS randomized phase III trial comparing brivanib vs. placebo (the first to prospectively incorporate mRECIST) were used to analyze objective response as a predictor of OS in a time-dependent covariate analysis. Patients with available imaging scans during follow-up were included (n=334; 85% of those randomized). Moreover, a correlation of the survival probability in deciles vs. the observed objective response was performed to evaluate its suitability as a surrogate end-point. RESULTS: Objective response was observed in 11.5% and 1.9% of patients treated with brivanib and placebo respectively, and was associated with a better survival (median OS 15.0 vs. 9.4months, p<0.001). In addition, objective response had an independent prognostic value (HR=0.48; 95% confidence interval [CI], 0.26-0.91, p=0.025) along with known prognostic factors. Finally, objective response showed promising results as a surrogate of OS in this trial (R=-0.92; 95% CI, -1 to -0.73, p<0.001). It was an early indicator of the treatment effect (median time to objective response was 1.4months). CONCLUSIONS: Objective response by mRECIST in advanced HCC predicts OS and thus can be considered as a candidate surrogate end-point. Further studies are needed to support this finding. LAY SUMMARY: There is a need to identify surrogate end-points for overall survival in advanced hepatocellular carcinoma. We studied patients from the phase III BRISK trial, comparing brivanib treatment with placebo after sorafenib progression. We demonstrate that objective response is an independent predictor of survival and qualifies as a potential surrogate end-point for overall survival in this patient population. CLINICAL TRIAL NUMBER: NCT00825955.

Description

Brivanib alaninate is an ATP-competitive inhibitor against VEGFR2 with an IC50 of 25 nM; has moderate potency against VEGFR-1 and FGFR-1, but more than 240-fold against PDGFRβ.

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