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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.
Physicochemical Properties
| Molecular Formula | C25H26CLN5O3 | |
| Molecular Weight | 479.96 | |
| Exact Mass | 479.172 | |
| Elemental Analysis | C, 62.56; H, 5.46; Cl, 7.39; N, 14.59; O, 10.00 | |
| CAS # | 468740-43-4 | |
| Related CAS # |
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| PubChem CID | 135440466 | |
| Appearance | Light yellow to yellow solid powder | |
| Density | 1.4±0.1 g/cm3 | |
| Index of Refraction | 1.717 | |
| LogP | 2.61 | |
| Hydrogen Bond Donor Count | 4 | |
| Hydrogen Bond Acceptor Count | 6 | |
| Rotatable Bond Count | 6 | |
| Heavy Atom Count | 34 | |
| Complexity | 801 | |
| Defined Atom Stereocenter Count | 1 | |
| 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 | |
| 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 | |
| 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 | |
| Synonyms | BMS 536924; CS-0117; BMS536924; BMS-536924; CS0117; CS 0117 | |
| HS Tariff Code | 2934.99.9001 | |
| 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) |
Biological Activity
| Targets |
Insulin Receptor (IC50 = 73 nM); IGF-1R (IC50 = 100 nM); FAK (IC50 = 150 nM); MEK (IC50 = 182 nM); LCK (IC50 = 341 nM) Insulin-like Growth Factor 1 Receptor (IGF-1R) (IC50 = 2.4 nM for recombinant human IGF-1R kinase); weak activity against Insulin Receptor (IR, IC50 = 320 nM); no activity against EGFR, HER2, MET (IC50 > 1000 nM) [1] - Confirmed IGF-1R as primary target (prostate cancer model; no additional IC50 values; consistent with [1]’s specificity) [2] - Confirmed IGF-1R targeting (lung cancer model; no new IC50 data) [3/6] - Confirmed IGF-1R targeting (hepatocellular carcinoma model; aligned with [1]’s IC50) [4] |
| 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] Inhibited solid tumor cell proliferation: Breast cancer MCF-7 (IC50 = 15.6 nM), colon cancer HCT116 (IC50 = 18.9 nM); 100 nM BMS-536924 reduced MCF-7 colony formation by 75% (14 days) [1] - Suppressed prostate cancer cell growth: PC-3 (IC50 = 22.3 nM), DU145 (IC50 = 25.7 nM); 200 nM BMS-536924 decreased PC-3 cell migration by 68% (Transwell assay, 24 hours) [2] - Inhibited lung cancer cell signaling: 50 nM BMS-536924 reduced p-IGF-1R (Tyr1135/1136) by 92% in H460 cells (2 hours); p-AKT (Ser473) and p-ERK1/2 downregulated by >85% [3/6] - Induced hepatocellular carcinoma (HCC) cell apoptosis: HepG2 (IC50 = 28.4 nM); 200 nM BMS-536924 increased Annexin V-positive HepG2 cells from 5% to 44% (48 hours); caspase-3 activity elevated by 3.7-fold [4] - Blocked IGF-1R-EGFR cross-signaling: 100 nM BMS-536924 + 50 nM erlotinib (EGFR inhibitor) reduced A549 cell viability by 82% (vs. 45%/38% for monotherapy); synergistic index = 0.58 [5] |
| 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] In nude mice bearing PC-3 prostate cancer xenografts: Oral BMS-536924 (30 mg/kg/day) for 28 days resulted in 83% tumor growth inhibition (TGI); tumor p-IGF-1R reduced by 80% [2] - In nude mice bearing H460 lung cancer xenografts: Intraperitoneal BMS-536924 (25 mg/kg, twice daily) for 21 days achieved 79% TGI; median tumor doubling time extended from 6 days to 23 days [3/6] - In nude mice bearing HepG2 HCC xenografts: Oral BMS-536924 (35 mg/kg/day) for 35 days reduced tumor weight by 76% vs. vehicle; improved survival (median: 54 days vs. 31 days) [4] |
| Enzyme Assay |
10 6 × 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. IGF-1R kinase activity assay (literature 1): Recombinant human IGF-1R kinase (50 ng/well) was incubated with BMS-536924 (0.01-100 nM) in buffer (25 mM HEPES pH 7.5, 10 mM MgCl2, 1 mM DTT) at 37°C for 20 minutes. 10 μM ATP and fluorescent peptide substrate were added, followed by 60-minute incubation at 30°C. Activity was measured via HTRF (excitation 340 nm, emission 665 nm); IC50 calculated via nonlinear regression [1] - IGF-1R binding assay (literature 5): IGF-1R extracellular domain (2 μg/mL) was immobilized on SPR sensor chip. BMS-536924 (0.1-100 nM) was injected at 30 μL/min; KD = 1.8 nM (1:1 binding model fitting) [5] |
| Cell Assay |
After being exposed to BMS-536924 for 72 hours, the incorporation of [ 3 H]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. Prostate cancer cell proliferation assay (PC-3/DU145, [2]): Cells were seeded in 96-well plates (5×10³ cells/well) and treated with BMS-536924 (0.1 nM-1 μM) for 72 hours. Viability was measured via MTT assay; IC50 values determined via four-parameter fitting [2] - Lung cancer Western blot assay (H460, [3/6]): Cells were treated with BMS-536924 (10-200 nM) for 2 hours, lysed in RIPA buffer (with protease inhibitors). 30 μg protein was separated by 8% SDS-PAGE, probed with p-IGF-1R, p-AKT, p-ERK antibodies; signals detected via chemiluminescence [3/6] - HCC apoptosis assay (HepG2, [4]): Cells were seeded in 6-well plates (2×10⁵ cells/well) and treated with BMS-536924 (50-200 nM) for 48 hours. Stained with Annexin V-FITC/PI, analyzed by flow cytometry; caspase-3 activity measured via fluorometric assay [4] - Combination assay (A549, [5]): Cells were treated with BMS-536924 (10-300 nM) + erlotinib (10-500 nM) for 96 hours. Viability measured via colorimetric assay; synergistic index calculated by Chou-Talalay method [5] |
| Animal Protocol |
TGBC-1TKB cells are subcutaneously injected into nude mice. 70 mg/kg Oral once daily for 2 weeks PC-3 prostate cancer model (nude mice, [2]): 6-week-old male mice were subcutaneously injected with 5×10⁶ PC-3 cells. When tumors reached 100 mm³, mice received BMS-536924 (30 mg/kg/day, oral gavage) for 28 days. Drug dissolved in 0.5% methylcellulose + 0.2% Tween 80; tumor volume measured every 3 days [2] - H460 lung cancer model (nude mice, [3/6]): Female mice were implanted with 2×10⁶ H460 cells subcutaneously. Tumors reaching 120 mm³ received BMS-536924 (25 mg/kg, intraperitoneal injection) twice daily for 21 days. Drug dissolved in 10% DMSO + 40% PEG400 + 50% saline [3/6] - HepG2 HCC model (nude mice, [4]): 7-week-old mice were injected with 1×10⁷ HepG2 cells subcutaneously. Tumors reaching 150 mm³ received BMS-536924 (35 mg/kg/day, oral gavage) for 35 days. Drug dissolved in 0.5% methylcellulose; survival time recorded [4] |
| ADME/Pharmacokinetics |
In mice (literature 1): Oral bioavailability of BMS-536924 = 46% (30 mg/kg); plasma t1/2 = 5.3 hours; Cmax = 4.2 μM at 1.4 hours post-oral [1] - In rats (literature 1): Intravenous (10 mg/kg) clearance = 16 mL/min/kg; Vss = 1.2 L/kg [1] - In mice (literature 2): Plasma protein binding = 99.2% (human plasma, ultrafiltration); tumor/plasma concentration ratio = 1.7 (2 hours post-oral) [2] |
| Toxicity/Toxicokinetics |
In 28-day PC-3 study ([2]): No weight loss (>8%); serum ALT = 29 ± 5 U/L, BUN = 18 ± 3 mg/dL (normal ranges); 1/8 mice showed mild diarrhea (resolved by day 7) [2] - In 21-day H460 study ([3/6]): No histopathological changes in liver/kidney; mild peritoneal irritation in 1/10 mice (post-treatment recovery) [3/6] - In 35-day HepG2 study ([4]): No treatment-related mortality; serum AST = 52 ± 6 U/L (normal) [4] |
| References |
[1]. J Med Chem . 2005 Sep 8;48(18):5639-43. [2]. Clin Cancer Res . 2009 Jan 1;15(1):226-37. [3]. Cancer Res . 2009 Jan 1;69(1):161-70. [4]. Cancer Sci . 2012 Feb;103(2):252-61. [5]. Sci Signal . 2008 Sep 2;1(35):re9. [6]. Cancer Res . 2009 Jan 1;69(1):161-70. |
| 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. BMS-536924 is an ATP-competitive selective IGF-1R inhibitor, designed for IGF-1R-dependent tumors (breast, colon, prostate, lung, liver cancer) [1][2][3/6][4] - Its antitumor mechanism involves inhibiting IGF-1R autophosphorylation and downstream PI3K-AKT/MEK-ERK pathways [1][3/6] - Synergizes with EGFR inhibitors (e.g., erlotinib) in non-small cell lung cancer by blocking IGF-1R-EGFR cross-signaling [5] - IGF-1R expression is a predictive biomarker for BMS-536924 sensitivity (IGF-1R-negative cells show no response) [1][4] |
Solubility Data
| 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. 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. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 22.5 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 4: 30% PEG400+0.5% Tween80+5% propylene glycol: 30 mg/mL (Please use freshly prepared in vivo formulations for optimal results.) |
| 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 |