WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 406172
CAS#: 940310-85-0
Description: NVP-BHG712, also known as BHG-712, is a EphB4 kinase inhibitor and BCR-ABL inhibitor. NVP-BHG712 inhibits EphB4 kinase activity in the low nanomolar range in cellular assays showed high selectivity for targeting the EphB4 kinase when profiled against other kinases in biochemical as well as in cell based assays. BHG-712 shows excellent pharmacokinetic properties and potently inhibits EphB4 autophosphorylation in tissues after oral administration.
MedKoo Cat#: 406172
Name: NVP-BHG712
CAS#: 940310-85-0
Chemical Formula: C26H20F3N7O
Exact Mass: 503.1681
Molecular Weight: 503.4892
Elemental Analysis: C, 62.02; H, 4.00; F, 11.32; N, 19.47; O, 3.18
Synonym: NVP BHG712; NVP BHG-712; NVP BHG 712; BHG-712; BHG712; BHG 712.
IUPAC/Chemical Name: 4-methyl-3-(1-methyl-6-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-N-(3-(trifluoromethyl)phenyl)benzamide
InChi Key: ZCCPLJOKGAACRT-UHFFFAOYSA-N
InChi Code: InChI=1S/C26H20F3N7O/c1-15-8-9-16(25(37)32-19-7-3-6-18(12-19)26(27,28)29)11-21(15)33-23-20-14-31-36(2)24(20)35-22(34-23)17-5-4-10-30-13-17/h3-14H,1-2H3,(H,32,37)(H,33,34,35)
SMILES Code: O=C(NC1=CC=CC(C(F)(F)F)=C1)C2=CC=C(C)C(NC3=C4C(N(C)N=C4)=NC(C5=CC=CN=C5)=N3)=C2
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
| Biological target: | NVP-BHG712 is an oral active EphB4 kinase autophosphorylation inhibitor. |
| In vitro activity: | Cells were then incubated in osteogenic induction medium supplemented with 200 nM NVP-BHG712 and/or 0.5 ng/ml TNF-α. MC3T3-E1 cells cultured in osteogenic induction medium served as controls. Seven days or 14 days after the treatment, this study found that NVP-BHG712 treatment significantly down-regulated TNF-α-stimulated ALP activity in MC3T3-E1 cells (Fig. 5a). Interestingly, 0.5 ng/ml TNF-α-stimulated TNFR2 expression was also partly reversed when EphB4 forward signaling was inhibited by NVP-BHG712 treatment (Figs. 5b-e), signifying that TNF-α-enhanced EphB4 signaling up-regulates TNFR2 expression. Reference: BMC Mol Cell Biol. 2020 Apr 16;21(1):29. https://pubmed.ncbi.nlm.nih.gov/32299362/ |
| In vivo activity: | This study used ovarian xenograft mouse model to evaluate the underlying resistance mechanisms of BV (bevacizumab) in ovarian cancer treatment. The results showed that EphB4 was overexpressed in BV-resistant xenograft models instead of other common receptor tyrosine kinases. In addition, when coadministrated with EphB4 blocker NVP-BHG712, the antitumor effect of BV was significantly enhanced in the resistant model, further confirmed the role of EphB4 in BV-resistant ovarian cancer. These results indicate that NVP-BHG712 reverses EphB4 overexpression-mediated resistance to BV. Reference: J Cancer Res Ther. 2019 Oct-Dec;15(6):1282-1287. https://pubmed.ncbi.nlm.nih.gov/31898661/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMF | 20.0 | 39.72 | |
| DMSO | 50.75 | 100.8 | |
| DMSO:PBS (pH 7.2) (1:2) | 0.33 | 0.66 | |
| Ethanol | 2.5 | 4.97 |
The following data is based on the product molecular weight 503.4892 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. Zhang Y, Yang C, Ge S, Wang L, Zhang J, Yang P. EphB4/ TNFR2/ERK/MAPK signaling pathway comprises a signaling axis to mediate the positive effect of TNF-α on osteogenic differentiation. BMC Mol Cell Biol. 2020 Apr 16;21(1):29. doi: 10.1186/s12860-020-00273-2. PMID: 32299362; PMCID: PMC7164363. 2. Rudzitis-Auth J, Fuß SA, Becker V, Menger MD, Laschke MW. Inhibition of erythropoietin-producing hepatoma receptor B4 (EphB4) signalling suppresses the vascularisation and growth of endometriotic lesions. Br J Pharmacol. 2020 Jul;177(14):3225-3239. doi: 10.1111/bph.15044. Epub 2020 Apr 12. PMID: 32144768; PMCID: PMC7312277. 3. Li L, Nan F, Guo Q, Guan D, Zhou C. Resistance to bevacizumab in ovarian cancer SKOV3 xenograft due to EphB4 overexpression. J Cancer Res Ther. 2019 Oct-Dec;15(6):1282-1287. doi: 10.4103/0973-1482.204896. PMID: 31898661. 4. Martiny-Baron G, Holzer P, Billy E, Schnell C, Brueggen J, Ferretti M, Schmiedeberg N, Wood JM, Furet P, Imbach P. The small molecule specific EphB4 kinase inhibitor NVP-BHG712 inhibits VEGF driven angiogenesis. Angiogenesis. 2010 Sep;13(3):259-67. doi: 10.1007/s10456-010-9183-z. Epub 2010 Aug 29. PMID: 20803239; PMCID: PMC2941628. |
| In vitro protocol: | 1. Zhang Y, Yang C, Ge S, Wang L, Zhang J, Yang P. EphB4/ TNFR2/ERK/MAPK signaling pathway comprises a signaling axis to mediate the positive effect of TNF-α on osteogenic differentiation. BMC Mol Cell Biol. 2020 Apr 16;21(1):29. doi: 10.1186/s12860-020-00273-2. PMID: 32299362; PMCID: PMC7164363. 2. Rudzitis-Auth J, Fuß SA, Becker V, Menger MD, Laschke MW. Inhibition of erythropoietin-producing hepatoma receptor B4 (EphB4) signalling suppresses the vascularisation and growth of endometriotic lesions. Br J Pharmacol. 2020 Jul;177(14):3225-3239. doi: 10.1111/bph.15044. Epub 2020 Apr 12. PMID: 32144768; PMCID: PMC7312277. |
| In vivo protocol: | 1. Li L, Nan F, Guo Q, Guan D, Zhou C. Resistance to bevacizumab in ovarian cancer SKOV3 xenograft due to EphB4 overexpression. J Cancer Res Ther. 2019 Oct-Dec;15(6):1282-1287. doi: 10.4103/0973-1482.204896. PMID: 31898661. 2. Martiny-Baron G, Holzer P, Billy E, Schnell C, Brueggen J, Ferretti M, Schmiedeberg N, Wood JM, Furet P, Imbach P. The small molecule specific EphB4 kinase inhibitor NVP-BHG712 inhibits VEGF driven angiogenesis. Angiogenesis. 2010 Sep;13(3):259-67. doi: 10.1007/s10456-010-9183-z. Epub 2010 Aug 29. PMID: 20803239; PMCID: PMC2941628. |
1: Li T, Wang H, Liu R, Wang X, Huang L, Wu Z, Yin X, Zou S, Duan P. The role of EphB4/ephrinB2 signaling in root repair after orthodontically-induced root resorption. Am J Orthod Dentofacial Orthop. 2021 Mar;159(3):e217-e232. doi: 10.1016/j.ajodo.2020.07.035. Epub 2021 Jan 22. PMID: 33487501.
2: Neuber C, Tröster A, Löser R, Belter B, Schwalbe H, Pietzsch J. The Pyrazolo[3,4-d]pyrimidine-Based Kinase Inhibitor NVP-BHG712: Effects of Regioisomers on Tumor Growth, Perfusion, and Hypoxia in EphB4-Positive A375 Melanoma Xenografts. Molecules. 2020 Nov 3;25(21):5115. doi: 10.3390/molecules25215115. PMID: 33153234; PMCID: PMC7662635.
3: Broggini T, Piffko A, Hoffmann CJ, Ghori A, Harms C, Adams RH, Vajkoczy P, Czabanka M. Ephrin-B2-EphB4 communication mediates tumor-endothelial cell interactions during hematogenous spread to spinal bone in a melanoma metastasis model. Oncogene. 2020 Nov;39(47):7063-7075. doi: 10.1038/s41388-020-01473-y. Epub 2020 Sep 28. PMID: 32989254.
4: Wan X, Saban DV, Kim SN, Weng Y, Dammann P, Keyvani K, Sure U, Zhu Y. PDCD10-Deficiency Promotes Malignant Behaviors and Tumor Growth via Triggering EphB4 Kinase Activity in Glioblastoma. Front Oncol. 2020 Aug 7;10:1377. doi: 10.3389/fonc.2020.01377. PMID: 32850441; PMCID: PMC7427606.
5: Andolfo I, Lasorsa VA, Manna F, Rosato BE, Formicola D, Iolascon A, Capasso M. Kinome multigenic panel identified novel druggable EPHB4-V871I somatic variant in high-risk neuroblastoma. J Cell Mol Med. 2020 Jun;24(11):6459-6471. doi: 10.1111/jcmm.15297. Epub 2020 Apr 26. PMID: 32336043; PMCID: PMC7294133.
6: Zhang Y, Yang C, Ge S, Wang L, Zhang J, Yang P. EphB4/ TNFR2/ERK/MAPK signaling pathway comprises a signaling axis to mediate the positive effect of TNF-α on osteogenic differentiation. BMC Mol Cell Biol. 2020 Apr 16;21(1):29. doi: 10.1186/s12860-020-00273-2. PMID: 32299362; PMCID: PMC7164363.
7: Rudzitis-Auth J, Fuß SA, Becker V, Menger MD, Laschke MW. Inhibition of erythropoietin-producing hepatoma receptor B4 (EphB4) signalling suppresses the vascularisation and growth of endometriotic lesions. Br J Pharmacol. 2020 Jul;177(14):3225-3239. doi: 10.1111/bph.15044. Epub 2020 Apr 12. PMID: 32144768; PMCID: PMC7312277.
8: Li L, Nan F, Guo Q, Guan D, Zhou C. Resistance to bevacizumab in ovarian cancer SKOV3 xenograft due to EphB4 overexpression. J Cancer Res Ther. 2019 Oct- Dec;15(6):1282-1287. doi: 10.4103/0973-1482.204896. PMID: 31898661.
9: Shi X, Zhu M, Gong Z, Yang T, Yu R, Wang J, Zhang Y. Homoharringtonine suppresses LoVo cell growth by inhibiting EphB4 and the PI3K/AKT and MAPK/EKR1/2 signaling pathways. Food Chem Toxicol. 2020 Feb;136:110960. doi: 10.1016/j.fct.2019.110960. Epub 2019 Nov 11. PMID: 31726078.
10: DiPrima M, Wang D, Tröster A, Maric D, Terrades-Garcia N, Ha T, Kwak H, Sanchez-Martin D, Kudlinzki D, Schwalbe H, Tosato G. Identification of Eph receptor signaling as a regulator of autophagy and a therapeutic target in colorectal carcinoma. Mol Oncol. 2019 Nov;13(11):2441-2459. doi: 10.1002/1878-0261.12576. Epub 2019 Oct 23. PMID: 31545551; PMCID: PMC6822245.
11: Tröster A, Heinzlmeir S, Berger BT, Gande SL, Saxena K, Sreeramulu S, Linhard V, Nasiri AH, Bolte M, Müller S, Kuster B, Médard G, Kudlinzki D, Schwalbe H. NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. ChemMedChem. 2018 Aug 20;13(16):1629-1633. doi: 10.1002/cmdc.201800398. Epub 2018 Jul 20. PMID: 29928781.
12: You C, Zhao K, Dammann P, Keyvani K, Kreitschmann-Andermahr I, Sure U, Zhu Y. EphB4 forward signalling mediates angiogenesis caused by CCM3/PDCD10-ablation. J Cell Mol Med. 2017 Sep;21(9):1848-1858. doi: 10.1111/jcmm.13105. Epub 2017 Apr 1. PMID: 28371279; PMCID: PMC5571521.
13: Wang M, Collins MJ, Foster TR, Bai H, Hashimoto T, Santana JM, Shu C, Dardik A. Eph-B4 mediates vein graft adaptation by regulation of endothelial nitric oxide synthase. J Vasc Surg. 2017 Jan;65(1):179-189. doi: 10.1016/j.jvs.2015.11.041. Epub 2016 Jan 24. PMID: 26817610; PMCID: PMC4958608.
14: Kathawala RJ, Wei L, Anreddy N, Chen K, Patel A, Alqahtani S, Zhang YK, Wang YJ, Sodani K, Kaddoumi A, Ashby CR Jr, Chen ZS. The small molecule tyrosine kinase inhibitor NVP-BHG712 antagonizes ABCC10-mediated paclitaxel resistance: a preclinical and pharmacokinetic study. Oncotarget. 2015 Jan 1;6(1):510-21. doi: 10.18632/oncotarget.2638. PMID: 25402202; PMCID: PMC4381611.
15: Becerikli M, Merwart B, Lam MC, Suppelna P, Rittig A, Mirmohammedsadegh A, Stricker I, Theiss C, Singer BB, Jacobsen F, Steinstraesser L. EPHB4 tyrosine- kinase receptor expression and biological significance in soft tissue sarcoma. Int J Cancer. 2015 Apr 15;136(8):1781-91. doi: 10.1002/ijc.29244. Epub 2014 Oct 18. PMID: 25274141.
16: Martiny-Baron G, Holzer P, Billy E, Schnell C, Brueggen J, Ferretti M, Schmiedeberg N, Wood JM, Furet P, Imbach P. The small molecule specific EphB4 kinase inhibitor NVP-BHG712 inhibits VEGF driven angiogenesis. Angiogenesis. 2010 Sep;13(3):259-67. doi: 10.1007/s10456-010-9183-z. Epub 2010 Aug 29. PMID: 20803239; PMCID: PMC2941628.
