WARNING: This product is for research use only, not for human or veterinary use.
Hodoodo CAT#: H200527
CAS#: 1025720-94-8
Description: BMS-777607, also known as BMS-817378 and ASLAN-002, a Met tyrosine kinase inhibitor, is an inhibitor of MET tyrosine kinase with potential antineoplastic activity. MET tyrosine kinase inhibitor BMS-777607 binds to c-Met protein, or hepatocyte growth factor receptor (HGFR), preventing binding of hepatocyte growth factor (HGF) and disrupting the MET signaling pathway; this agent may induce cell death in tumor cells expressing c-Met. c-Met, a receptor tyrosine kinase overexpressed or mutated in many tumor cell types, plays an important role in tumor cell proliferation, survival, invasion, and metastasis, and in tumor angiogenesis.
Hodoodo Cat#: H200527
Name: BMS-777607
CAS#: 1025720-94-8
Chemical Formula: C25H19ClF2N4O4
Exact Mass: 512.11
Molecular Weight: 512.890
Elemental Analysis: C, 58.54; H, 3.73; Cl, 6.91; F, 7.41; N, 10.92; O, 12.48
Related CAS #: 1025720-94-8 1196681-44-3 (deleted)
Synonym: BMS817378; BMS 817378; BMS-817378; BMS 777607; BMS-777607; BMS777607; ASLAN 002; ASLAN-002; ASLAN002.
IUPAC/Chemical Name: N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide.
InChi Key: VNBRGSXVFBYQNN-UHFFFAOYSA-N
InChi Code: InChI=1S/C25H19ClF2N4O4/c1-2-35-19-10-12-32(16-6-3-14(27)4-7-16)25(34)21(19)24(33)31-15-5-8-18(17(28)13-15)36-20-9-11-30-23(29)22(20)26/h3-13H,2H2,1H3,(H2,29,30)(H,31,33)
SMILES Code: O=C(C1=C(OCC)C=CN(C2=CC=C(F)C=C2)C1=O)NC3=CC=C(OC4=C(Cl)C(N)=NC=C4)C(F)=C3
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 at 40mg / mL, not soluble in water, not soluble in ethanol.
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
More Info:
| Biological target: | BMS 777607 is a Met-related inhibitor for c-Met, Axl, Ron and Tyro3 with IC50s of 3.9 nM, 1.1 nM, 1.8 nM and 4.3 nM, respectively. |
| In vitro activity: | This study performed flow cytometry analysis of Hs578T cells after stimulation of AXL by exogenous GAS6 for 30 min and 2 hours, in combination with BMS77607 treatment. Two different extra-cellularly binding anti-AXL antibodies were used, namely Ab 154 and Ab 259/2. This study analyzed the cell surface expression without cell membrane permeabilisation and total AXL abundance of Hs578T cell after cell membrane permeabilisation. Exogenous GAS6 stimulation resulted in a significant cell surface and total AXL depletion within 2 h to 50% or 60%. 0.5 μM BMS (BMS 777607) completely abolished the depletion of AXL from the cell surface (Fig. 5a-b). This study shows that internalization of AXL is suppressed by BMS and assumed that this is caused by inhibition of AXL ubiquitination (Fig. 5c-f). Reference: Cell Commun Signal. 2019; 17: 59. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555758/ |
| In vivo activity: | Here, BMS-777607 with an intermittent low-dose administration led to an augmentation of bone callus in mice after a standardized femur osteotomy. On the basis of the radiological analysis data, BMS-777607 could induce the rapid formation of a callus during the early stage of fracture healing, and this effect provides initial stabilization to help the bone heal more quickly. Even though the callus size was different between the two groups at week 3, there was no distinct structural modification because of the existence of integrity external collars in both groups. Moreover, Safranin O staining indicated BMS-777607 promoted early rapid proliferation of an exterior callus, which suggested that BMS-777607 played a crucial role in intramembranous ossification during external callus formation, thus reflecting that osteoblast proliferation and differentiation was the major target. Reference: Exp Cell Res. 2019 Aug 1;381(1):50-56. https://pubmed.ncbi.nlm.nih.gov/31034806/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 48.0 | 93.59 | |
| DMF | 20.0 | 38.99 | |
| DMF:PBS (pH 7.2) (1:7) | 0.1 | 0.19 |
The following data is based on the product molecular weight 512.89 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. Lauter M, Weber A, Torka R. Targeting of the AXL receptor tyrosine kinase by small molecule inhibitor leads to AXL cell surface accumulation by impairing the ubiquitin-dependent receptor degradation. Cell Commun Signal. 2019 Jun 6;17(1):59. doi: 10.1186/s12964-019-0377-8. PMID: 31171001; PMCID: PMC6555758. 2. Wu CC, Weng CS, Hsu YT, Chang CL. Antitumor effects of BMS-777607 on ovarian cancer cells with constitutively activated c-MET. Taiwan J Obstet Gynecol. 2019 Jan;58(1):145-152. doi: 10.1016/j.tjog.2018.11.027. PMID: 30638469. 3. Wang R, Xu X, Li Y, Li J, Yao C, Wu R, Jiang Q, Shi D. A C-Met chemical inhibitor promotes fracture healing through interacting with osteogenic differentiation via the mTORC1 pathway. Exp Cell Res. 2019 Aug 1;381(1):50-56. doi: 10.1016/j.yexcr.2019.03.037. Epub 2019 Apr 26. PMID: 31034806. 4. Khaibullina A, Adjei EA, Afangbedji N, Ivanov A, Kumari N, Almeida LEF, Quezado ZMN, Nekhai S, Jerebtsova M. RON kinase inhibition reduces renal endothelial injury in sickle cell disease mice. Haematologica. 2018 May;103(5):787-798. doi: 10.3324/haematol.2017.180992. Epub 2018 Mar 8. PMID: 29519868; PMCID: PMC5927980. |
| In vitro protocol: | 1. Lauter M, Weber A, Torka R. Targeting of the AXL receptor tyrosine kinase by small molecule inhibitor leads to AXL cell surface accumulation by impairing the ubiquitin-dependent receptor degradation. Cell Commun Signal. 2019 Jun 6;17(1):59. doi: 10.1186/s12964-019-0377-8. PMID: 31171001; PMCID: PMC6555758. 2. Wu CC, Weng CS, Hsu YT, Chang CL. Antitumor effects of BMS-777607 on ovarian cancer cells with constitutively activated c-MET. Taiwan J Obstet Gynecol. 2019 Jan;58(1):145-152. doi: 10.1016/j.tjog.2018.11.027. PMID: 30638469. |
| In vivo protocol: | 1. Wang R, Xu X, Li Y, Li J, Yao C, Wu R, Jiang Q, Shi D. A C-Met chemical inhibitor promotes fracture healing through interacting with osteogenic differentiation via the mTORC1 pathway. Exp Cell Res. 2019 Aug 1;381(1):50-56. doi: 10.1016/j.yexcr.2019.03.037. Epub 2019 Apr 26. PMID: 31034806. 2. Khaibullina A, Adjei EA, Afangbedji N, Ivanov A, Kumari N, Almeida LEF, Quezado ZMN, Nekhai S, Jerebtsova M. RON kinase inhibition reduces renal endothelial injury in sickle cell disease mice. Haematologica. 2018 May;103(5):787-798. doi: 10.3324/haematol.2017.180992. Epub 2018 Mar 8. PMID: 29519868; PMCID: PMC5927980. |
1: Onken J, Torka R, Korsing S, Radke J, Krementeskaia I, Nieminen M, Bai X, Ullrich A, Heppner F, Vajkoczy P. Inhibiting receptor tyrosine kinase AXL with small molecule inhibitor BMS-777607 reduces glioblastoma growth, migration, and invasion in vitro and in vivo. Oncotarget. 2016 Mar 1;7(9):9876-89. doi: 10.18632/oncotarget.7130. PubMed PMID: 26848524.
2: Chakedis J, French R, Babicky M, Jaquish D, Howard H, Mose E, Lam R, Holman P, Miyamoto J, Walterscheid Z, Lowy AM. A novel protein isoform of the RON tyrosine kinase receptor transforms human pancreatic duct epithelial cells. Oncogene. 2015 Oct 19. doi: 10.1038/onc.2015.384. [Epub ahead of print] PubMed PMID: 26477314; PubMed Central PMCID: PMC4837108.
3: Müller J, Krijgsman O, Tsoi J, Robert L, Hugo W, Song C, Kong X, Possik PA, Cornelissen-Steijger PD, Foppen MH, Kemper K, Goding CR, McDermott U, Blank C, Haanen J, Graeber TG, Ribas A, Lo RS, Peeper DS. Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma. Nat Commun. 2014 Dec 15;5:5712. doi: 10.1038/ncomms6712. PubMed PMID: 25502142; PubMed Central PMCID: PMC4428333.
4: Nurhayati RW, Ojima Y, Taya M. BMS-777607 promotes megakaryocytic differentiation and induces polyploidization in the CHRF-288-11 cells. Hum Cell. 2015 Apr;28(2):65-72. doi: 10.1007/s13577-014-0102-2. Epub 2014 Oct 11. PubMed PMID: 25304900.
5: Zhang W, Ai J, Shi D, Peng X, Ji Y, Liu J, Geng M, Li Y. Discovery of novel type II c-Met inhibitors based on BMS-777607. Eur J Med Chem. 2014 Jun 10;80:254-66. doi: 10.1016/j.ejmech.2014.04.056. Epub 2014 Apr 21. PubMed PMID: 24792774.
6: Szokol B, Gyulavári P, Baska F, Ibolya K, Greff Z, Szántai KC, Zoltán O, Peták I, Axel U, Vantus T, Kéri G, Orfi L. [Development and biochemical characterization of EGFR/c-Met dual inhibitors]. Acta Pharm Hung. 2013;83(4):121-33. Hungarian. PubMed PMID: 24575658.
7: Zhang W, Ai J, Shi D, Peng X, Ji Y, Liu J, Geng M, Li Y. Discovery of novel c-Met inhibitors bearing a 3-carboxyl piperidin-2-one scaffold. Molecules. 2014 Feb 24;19(2):2655-73. doi: 10.3390/molecules19022655. PubMed PMID: 24566328.
8: Sharma S, Yao HP, Zhou YQ, Zhou J, Zhang R, Wang MH. Prevention of BMS-777607-induced polyploidy/senescence by mTOR inhibitor AZD8055 sensitizes breast cancer cells to cytotoxic chemotherapeutics. Mol Oncol. 2014 May;8(3):469-82. doi: 10.1016/j.molonc.2013.12.014. Epub 2014 Jan 2. PubMed PMID: 24444656.
9: Traoré T, Cavagnino A, Saettel N, Radvanyi F, Piguel S, Bernard-Pierrot I, Stoven V, Legraverend M. New aminopyrimidine derivatives as inhibitors of the TAM family. Eur J Med Chem. 2013;70:789-801. doi: 10.1016/j.ejmech.2013.10.037. Epub 2013 Oct 22. PubMed PMID: 24239626.
10: Zeng JY, Sharma S, Zhou YQ, Yao HP, Hu X, Zhang R, Wang MH. Synergistic activities of MET/RON inhibitor BMS-777607 and mTOR inhibitor AZD8055 to polyploid cells derived from pancreatic cancer and cancer stem cells. Mol Cancer Ther. 2014 Jan;13(1):37-48. doi: 10.1158/1535-7163.MCT-13-0242. Epub 2013 Nov 14. PubMed PMID: 24233399.
11: Sharma S, Zeng JY, Zhuang CM, Zhou YQ, Yao HP, Hu X, Zhang R, Wang MH. Small-molecule inhibitor BMS-777607 induces breast cancer cell polyploidy with increased resistance to cytotoxic chemotherapy agents. Mol Cancer Ther. 2013 May;12(5):725-36. doi: 10.1158/1535-7163.MCT-12-1079. Epub 2013 Mar 6. PubMed PMID: 23468529.
12: Voortman J, Harada T, Chang RP, Killian JK, Suuriniemi M, Smith WI, Meltzer PS, Lucchi M, Wang Y, Giaccone G. Detection and therapeutic implications of c-Met mutations in small cell lung cancer and neuroendocrine tumors. Curr Pharm Des. 2013;19(5):833-40. PubMed PMID: 22973954.
13: Gujral TS, Karp RL, Finski A, Chan M, Schwartz PE, MacBeath G, Sorger P. Profiling phospho-signaling networks in breast cancer using reverse-phase protein arrays. Oncogene. 2013 Jul 18;32(29):3470-6. doi: 10.1038/onc.2012.378. Epub 2012 Sep 3. PubMed PMID: 22945653; PubMed Central PMCID: PMC3670968.
14: Suárez RM, Chevot F, Cavagnino A, Saettel N, Radvanyi F, Piguel S, Bernard-Pierrot I, Stoven V, Legraverend M. Inhibitors of the TAM subfamily of tyrosine kinases: synthesis and biological evaluation. Eur J Med Chem. 2013 Mar;61:2-25. doi: 10.1016/j.ejmech.2012.06.005. Epub 2012 Jun 12. PubMed PMID: 22749189.
15: Dai Y, Siemann DW. Constitutively active c-Met kinase in PC-3 cells is autocrine-independent and can be blocked by the Met kinase inhibitor BMS-777607. BMC Cancer. 2012 May 28;12:198. doi: 10.1186/1471-2407-12-198. PubMed PMID: 22639908; PubMed Central PMCID: PMC3418572.
16: Dai Y, Bae K, Pampo C, Siemann DW. Impact of the small molecule Met inhibitor BMS-777607 on the metastatic process in a rodent tumor model with constitutive c-Met activation. Clin Exp Metastasis. 2012 Mar;29(3):253-61. doi: 10.1007/s10585-011-9447-z. PubMed PMID: 22286523.
17: Dai Y, Siemann DW. BMS-777607, a small-molecule met kinase inhibitor, suppresses hepatocyte growth factor-stimulated prostate cancer metastatic phenotype in vitro. Mol Cancer Ther. 2010 Jun;9(6):1554-61. doi: 10.1158/1535-7163.MCT-10-0359. Epub 2010 Jun 1. PubMed PMID: 20515943.
18: Schroeder GM, An Y, Cai ZW, Chen XT, Clark C, Cornelius LA, Dai J, Gullo-Brown J, Gupta A, Henley B, Hunt JT, Jeyaseelan R, Kamath A, Kim K, Lippy J, Lombardo LJ, Manne V, Oppenheimer S, Sack JS, Schmidt RJ, Shen G, Stefanski K, Tokarski JS, Trainor GL, Wautlet BS, Wei D, Williams DK, Zhang Y, Zhang Y, Fargnoli J, Borzilleri RM. Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl )-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily. J Med Chem. 2009 Mar 12;52(5):1251-4. doi: 10.1021/jm801586s. PubMed PMID: 19260711.
