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Purity: =98.85%
BMS-754807 (BMS754807) is an orally bioavailable small molecule inhibitor of IGF-1R/InsR (growth factor 1 receptor/insulin receptor family kinases) with potential antineoplastic activity. In cell-free assays, it inhibits IGF-1R/InsR with IC50s of 1.8 nM/1.7 nM. However, its potency against other kinases, including Met, PKA, Aurora A/B, Flt3, Lck, MK2, TrkA/B, Ron, and PKC, is lower. Excellent in vivo antitumor efficaciousness is demonstrated in nude mice with tumors of IGF-1R-Sal, GEO, Colo205, JJN3, RD1, or Rh41.
| Targets |
IR (IC50 = 1.7 nM); IGF-1R (IC50 = 1.8 nM); TrkB (IC50 = 4 nM); Met (IC50 = 6 nM); TrkA (IC50 = 7 nM); AurA (IC50 = 9 nM); AurB (IC50 = 25 nM); RON (IC50 = 44 nM)
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| Enzyme Assay |
Utilizing recombinant human IGF-1 receptor enzyme in biochemical assays with synthetic peptide KKSRGDYMTMQIG as a phosphoacceptor substrate, an in vitro kinase assay serves as the main screening method for BMS-754807. Multiple recombinant enzymes that are produced at BMS or acquired externally are used to assess the selectivity profile. Utilizing a 30 μL reaction volume in assay buffer (100 mM Hepes pH 7.4, 10 mM MgCl2, 0.015% Brij35, and 4 mM DTT), the enzymatic assays are carried out in Ubottom 384-well plates. The enzyme, BMS-754807, 1.5 μM fluorescein-labeled peptide substrate, and ATP (concentration equal to Km ATP) are combined to start the 60-minute reactions. With the use of EDTA, the reactions are stopped. The fluorescent substrate and phosphorylated product are separated electrophoretically and used to analyze the reaction mixtures on the Caliper LabChip 3000. For 100% inhibition, inhibition data are computed in relation to enzyme-free control reactions, and for 0% inhibition, vehicle-only reactions are used. Dimethylsulfoxide (DMSO, 10 mM stock) is used to dissolve the compounds, and eleven concentrations are tested. The dose response curves are analyzed using non-linear regression to determine the IC50 values.
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| Cell Assay |
The ideal growth medium for cells is RPMI +GlutaMax supplemented with 10% heat-inactivated fetal bovine serum (FBS), 10 mM Hepes, penicillin, and streptomycin. Following a 72-hour exposure of cells to BMS-754807, the incorporation of 3H-thymidine into DNA is used to assess the proliferation of the cells. The drug concentration needed to suppress cell proliferation by 50% in comparison to untreated control cells is known as the inhibitory concentration (IC50), and this is how results are expressed.
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| Animal Protocol |
Each animal is given a subcutaneous implant of a tumor fragment (approximately 20 mg) using a 13-gauge trocar once the necessary number of animals are gathered at the beginning of the experiment in order to detect a meaningful response. The size of tumors is allowed to grow up to 200 mg, and tumors larger than this range are removed. Animals are divided equally into treatment and control groups. Generally, eight mice are included in each treatment group and control group.However, experiments carried out using the Sal-IGF (also known as IGF-1R-Sal) tumor model typically involve five mice per treatment group and control group. Each animal's care is determined by its unique body weight. Every day, treated animals are examined for treatment-related toxicity and mortality. Weighing is done on each group of animals both prior to the start of treatment (Wt1) and after the final dose of treatment (Wt2). Treatment-related toxicity is measured by the difference in body weight (Wt2 − Wt1).
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| Additional Infomation |
BMS-754807 is a pyrrolotriazine that is pyrrolo[2,1-f][1,2,4]triazine which is substituted at position 2 by the pyrrolidine nitrogen of (2S)-N-(6-fluoropyridin-3-yl)-2-methylprolinamide, and at position 4 by a (5-cyclopropyl-1H-pyrazol-3-yl)amino group. It is a potent, reversible inhibitor of the insulin-like growth factor 1 receptor/insulin receptor family kinases. It has a role as an EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor and an antineoplastic agent. It is a pyrrolotriazine, a member of pyrazoles, a member of pyridines and a member of pyrrolidines.
BMS-754807 is under investigation in clinical trial NCT00908024 (Combination Study of BMS-754807 and Erbitux® in Subjects With Advanced or Metastatic Solid Tumors). Dual IGF-1R/InsR Inhibitor BMS-754807 is an oral small molecule inhibitor of insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (InsR) tyrosine kinases with potential antineoplastic activity. Dual IGF-IR/InsR inhibitor BMS-754807 binds reversibly to and inhibits the activities of IGF-1R and InsR, which may result in the inhibition of tumor cell proliferation and the induction of tumor cell apoptosis. IGF-1R and InsR tyrosine kinases, overexpressed in a variety of human cancers, play significant roles in mitogenesis, angiogenesis, and tumor cell survival. |
| Molecular Formula |
C23H24FN9O
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| Molecular Weight |
461.49
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| Exact Mass |
461.208
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| Elemental Analysis |
C, 59.86; H, 5.24; F, 4.12; N, 27.32; O, 3.47
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| CAS # |
1001350-96-4
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| Related CAS # |
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| PubChem CID |
24785538
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| Appearance |
White to off-white solid powder
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| Density |
1.6±0.1 g/cm3
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| Index of Refraction |
1.795
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| LogP |
1.76
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
34
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| Complexity |
756
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| Defined Atom Stereocenter Count |
1
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| SMILES |
FC1C([H])=C([H])C(=C([H])N=1)N([H])C([C@]1(C([H])([H])[H])C([H])([H])C([H])([H])C([H])([H])N1C1=NN2C([H])=C([H])C([H])=C2C(N([H])C2C([H])=C(C3([H])C([H])([H])C3([H])[H])N([H])N=2)=N1)=O
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| InChi Key |
LQVXSNNAFNGRAH-QHCPKHFHSA-N
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| InChi Code |
InChI=1S/C23H24FN9O/c1-23(21(34)26-15-7-8-18(24)25-13-15)9-3-10-32(23)22-28-20(17-4-2-11-33(17)31-22)27-19-12-16(29-30-19)14-5-6-14/h2,4,7-8,11-14H,3,5-6,9-10H2,1H3,(H,26,34)(H2,27,28,29,30,31)/t23-/m0/s1
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| Chemical Name |
(2S)-1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl]-N-(6-fluoropyridin-3-yl)-2-methylpyrrolidine-2-carboxamide
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| Synonyms |
BMS-754807; BMS 754807; BMS754807
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (5.42 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.51 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.51 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 2% DMSO+30% PEG 300+ddH2O: 5 mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1669 mL | 10.8345 mL | 21.6689 mL | |
| 5 mM | 0.4334 mL | 2.1669 mL | 4.3338 mL | |
| 10 mM | 0.2167 mL | 1.0834 mL | 2.1669 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00898716 | Completed | Drug: BMS-754807 | Neoplasms | Bristol-Myers Squibb | September 2009 | Phase 1 |
| NCT01525823 | Completed | Drug: BMS-754807 (IGR-IR/IR Inhibitor) Drug: Metformin |
Healthy Volunteers | Bristol-Myers Squibb | February 2012 | Phase 1 |
| NCT00569036 | Completed | Drug: BMS-754807 | Neoplasms Metastases |
Bristol-Myers Squibb | April 2008 | Phase 1 |
| NCT00788333 | Completed | Drug: BMS-754807 Drug: trastuzumab (Herceptin®) |
Breast Cancer | Bristol-Myers Squibb | July 2009 | Phase 1 Phase 2 |
| NCT00793897 | Completed | Drug: Paclitaxel Drug: BMS-754807 |
Advanced Solid Tumors Metastatic Solid Tumors |
Bristol-Myers Squibb | April 2009 | Phase 1 |
Cell cycle and induction of apoptosis in Rh41 cells exposed to BMS-754807, mAb391, and VX-680. Mol Cancer Ther. 2009 Dec;8(12):3341-9. |
Effects of BMS-754807 in vivo. Pharmacodynamic and pharmacokinetic study in IGF-1R-Sal–tumored mice. Mice were dosed with either 3.125 or 12.5 mpk, and serum and tumor samples were evaluated at multiple time points up to 24 h. Mol Cancer Ther. 2009 Dec;8(12):3341-9. |
Combination of BMS-754807 with cetuximab in vivo. Antitumor effect of BMS-754807 in combination with cetuximab on the growth of the GEO human colon carcinoma xenograft model in nude mice. Each symbol represents the median tumor weight of a group of eight mice. Triangles adjacent to the X-axis indicate the schedule of drug administration. Mol Cancer Ther. 2009 Dec;8(12):3341-9. |
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