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Purity: ≥98%
BMS-536924 (also called CS-0117; BMS536924; CS0117) is a novel, potent and ATP-competitive small molecule inhibitor of IGF-1R/IR with potential anticancer activity. With an IC50 of 100 nM/73 nM, it inhibits IGF-1R/IR. While BMS-536924 exhibited very little activity for Akt1, MAPK1/2, it did show modest activity against Mek, Fak, and Lck. In a number of tumor models, including the sarcoma and IGR-1R Sal tumor model, BMS-536924 demonstrates strong antitumor activity.
| Targets |
Insulin Receptor (IC50 = 73 nM); IGF-1R (IC50 = 100 nM); FAK (IC50 = 150 nM); MEK (IC50 = 182 nM); LCK (IC50 = 341 nM)
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| ln Vitro |
BMS-536924 also inhibits Lck and FAK, with IC50 values of 341 nM and 150 nM, respectively. BMS-536924 disrupts Akt and MAPK phosphorylation and inhibits the proliferation of cells. (Source: ) BMS-536924 inhibits constitutive IGF-1R activity in CD8-IGF-1R-MCF10A and suppresses IGF-I-stimulated IGF-1R signaling in MCF10A cells. The ability of IGF-I to stimulate IGF-1R phosphorylation is completely blocked when 1 μM BMS-536924 is preincubated with MCF10A cells. Increased phosphorylation of ERK1/2, GSK3β, and Akt is the outcome of IGF-I stimulation. BMS-536924 prevents this phosphorylation that is triggered by the ligand. BMS-536924 treatment of the CD8-IGF-1R-MCF10A cells inhibits phosphorylation in a dose-dependent manner, showing partial inhibition at 0.01 μM and 0.1 μM but complete receptor inhibition at 1 μM. As early as 10 minutes after incubation, the maximum inhibition of phosphorylated IGF-1R is seen. For as long as 48 hours, BMS-536924 can still prevent IGF-1R phosphorylation. After one hour, BMS-536924 is added, and this inhibits Akt phosphorylation in a time-dependent manner. After 48 hours, Akt activation is totally inhibited.[2] BMS-536924 treatment exhibits antiproliferation activity against a range of cancer cell lines, including CTR, HT1080/S, TC32, SK-LMS-1, and H513 cells. In Rh41 and Rh36 cell lines, pIGF-1R/pIR is activated in response to IGF-I/insulin stimulation, and the activation is blocked by BMS-536924 at comparable potencies. In Rh41 cells treated with BMS-536924, there is an up-regulation of the expression of caspase-3, cleavage of poly(ADP-ribose) polymerase (PARP), and programmed cell death 4 (PDCD4).[3]
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| ln Vivo |
BMS-536924 administered orally at 100–300 mpk significantly inhibits the IGR-1R Sal tumor model. The non-engineered Colo205 human colon carcinoma mode also demonstrates efficacy. In this tumor model, oral administration of 3 on a once daily schedule (100-300 mpk) or twice daily schedule (50, 100 mpk) exhibits antitumor activity. The oral glucose tolerance test (OGTT) demonstrates that following a glucose challenge, 100 mpk (b.i.d.) significantly raises blood glucose levels. The oral administration of BMS-536924 in a solution of poly(ethylene glycol) 400 and water (80:20 v/v) was used to determine the pharmacokinetic parameters in mice, rats, dogs, and monkeys. In all species, good bioavailability is apparent. In rodents, significant nonlinear pharmacokinetics are seen with increasing PO dosage. [1] After two weeks of treatment (100 mg/kg), BMS-536924 reduces the volume of CD8-IGF-1R-MCF10A cells in tumor xenografts to 76%.[2] When given orally to nude mice, 70 mg/kg of BMS-536924 significantly suppresses the growth of tumors (TGBC-1TKB cells) that have been injected. The xenograft tumors' apoptosis is upregulated by BMS-536924. The mice's body weight and blood glucose levels at the moment of death show no negative effects from the treatment, indicating tolerable toxicity.[4]
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| Enzyme Assay |
106 × 1 p On 60-mm dishes, Babe-MCF10A cells are seeded. The medium is switched to serum-free medium after the first 24 hours, and it is then incubated for an additional 24 hours at 37 °C. The cells are then stimulated with IGF-I (50 ng/mL) for 10 minutes after being pre-incubated for 1 hour in serum-free medium with or without 1 uM BMS-536924. After two PBS washes, cell monolayers are collected for immunoblot analysis.
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| Cell Assay |
After being exposed to BMS-536924 for 72 hours, the incorporation of [3H]thymidine is used to assess cell proliferation. Following an overnight incubation period at 37 °C, cells are plated at an optimal density in 96-well plates and subjected to a series of drug dilutions. After a 72-hours incubation, cells are pulsed with 4 μCi/mL [3H]thymidine for 3 hours, trypsinized, harvested onto UniFilter-96 GF/B plates; scintillation is measured on a TopCount NXT. The IC50 represents the results. For every cell line, the mean IC50 and SD from several tests are computed.
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| Animal Protocol |
TGBC-1TKB cells are subcutaneously injected into nude mice.
70 mg/kg Oral once daily for 2 weeks |
| References | |
| Additional Infomation |
4-[[(2S)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-[4-methyl-6-(4-morpholinyl)-1,3-dihydrobenzimidazol-2-ylidene]-2-pyridinone is a member of benzimidazoles.
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| Molecular Formula |
C25H26CLN5O3
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| Molecular Weight |
479.96
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| Exact Mass |
479.172
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| Elemental Analysis |
C, 62.56; H, 5.46; Cl, 7.39; N, 14.59; O, 10.00
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| CAS # |
468740-43-4
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| Related CAS # |
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| PubChem CID |
135440466
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.4±0.1 g/cm3
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| Index of Refraction |
1.717
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| LogP |
2.61
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
34
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| Complexity |
801
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| Defined Atom Stereocenter Count |
1
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| SMILES |
O=C1C(C2=NC3=CC(N4CCOCC4)=CC(C)=C3N2)=C(C=CN1)NC[C@@H](O)C5=CC=CC(Cl)=C5
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| InChi Key |
ZWVZORIKUNOTCS-OAQYLSRUSA-N
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| InChi Code |
InChI=1S/C25H26ClN5O3/c1-15-11-18(31-7-9-34-10-8-31)13-20-23(15)30-24(29-20)22-19(5-6-27-25(22)33)28-14-21(32)16-3-2-4-17(26)12-16/h2-6,11-13,21,32H,7-10,14H2,1H3,(H,29,30)(H2,27,28,33)/t21-/m1/s1
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| Chemical Name |
4-[[(2S)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-(4-methyl-6-morpholin-4-yl-1H-benzimidazol-2-yl)-1H-pyridin-2-one
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| Synonyms |
BMS 536924; CS-0117; BMS536924; BMS-536924; CS0117; CS 0117
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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: ≥ 3.75 mg/mL (7.81 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 37.5 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.21 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. View More
Solubility in Formulation 3: ≥ 2.25 mg/mL (4.69 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 30% PEG400+0.5% Tween80+5% propylene glycol: 30 mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0835 mL | 10.4175 mL | 20.8351 mL | |
| 5 mM | 0.4167 mL | 2.0835 mL | 4.1670 mL | |
| 10 mM | 0.2084 mL | 1.0418 mL | 2.0835 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.
BMS-536924 inhibits IGF-IR signaling in pBabe-MCF10A cells and inhibits phosphorylation of CD8-IGF-IR. Clin Cancer Res. 2009 Jan 1;15(1):226-37. |
BMS-536924 inhibits transformation in vitro and in vivo. Clin Cancer Res. 2009 Jan 1;15(1):226-37. |
BMS-536924 decreases proliferation and cell number in MCF7 and MDAMB-435 acini and reverses MCF7 acini formation. Clin Cancer Res. 2009 Jan 1;15(1):226-37. |
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