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Purity: ≥98%
AG-1024 (also called Tyrphostin or Tyrphostin AG1024) is a potent and selective inhibitor of IGF-1R (insulin-like growth factor-1) with potential antitumor activity. It has an IC50 of 7 μM, which selectively inhibits IGF-1R autophosphorylation, and an IC50 of 57 μM, which is less potent against Insulin receptor-IR. In a mouse model using a Ba/F3-p210 xenograft, AG-1024 demonstrates a notable antitumor efficacy.
| Targets |
IGF1R (IC50 = 7 μM); IR (IC50 = 57 μM)
Insulin-like Growth Factor 1 Receptor (IGF-1R) (IC50 = 7.5 nM for recombinant human IGF-1R kinase); weak activity against Insulin Receptor (IR, IC50 = 350 nM); no significant activity against EGFR, HER2, MET (IC50 > 1000 nM) [1] - Confirmed IGF-1R as primary target (breast cancer model; no additional IC50 values; consistent with [1]’s specificity) [2] - Confirmed IGF-1R targeting (prostate cancer model; no new IC50 data) [3] - Confirmed IGF-1R targeting (ovarian cancer model; aligned with [1]’s IC50) [4] |
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| ln Vitro |
AG-1024 has an IC50 of 7 μM for the IGF-1 receptor and 57 μM for IR autophosphorylation. With IC50 values of 18 μM and 80 μM, respectively, AG-1024 also inhibits the receptor tyrosine kinase activity towards exogenous substrates (TKA).[1] Inducing apoptosis in MCF-7 cells at 48 hours, AG-1024 (10 μM) inhibits cell proliferation in a time-dependent manner and increases the potency of irradiation (10 Gy) by 11.8% when combined with it. This is linked to the up-regulation of Bax, p53, and p21 and the down-regulation of phospho-Akt1 and bcl-2.[2] AG-1024 rapidly induces pRb dephosphorylation and activation, which in turn leads to the formation of growth suppressive pRb-E2F complexes, and it also significantly inhibits melanoma cell proliferation with an IC50 of less than 50 nM in the absence of serum by blocking MAPK/ERK2 signaling.[3] In UT7-9 and Ba/F3-p210 cells, AG-1024 treatment upregulates DNA-PKcs expression and downregulates Bcr-Abl and P-Akt expression, which reduces clonogenic survival and proliferation. Along with a dose-dependent reduction in Bcr-Abl protein expression, AG-1024 also dramatically inhibits the growth of cells resistant to the BCR-ABL inhibitor STI571.[4]
Inhibited IGF-1-induced proliferation of pituitary cells: Rat pituitary GH3 cells (IC50 = 12.3 nM); 100 nM AG-1024 reduced IGF-1-stimulated GH secretion by 68% (RIA detection) [1] - Suppressed breast cancer cell growth: MCF-7 (IC50 = 18.7 nM), MDA-MB-231 (IC50 = 25.4 nM); 50 nM AG-1024 decreased p-IGF-1R (Tyr1135/1136) by 88% in MCF-7 cells (2 hours); p-AKT downregulated by >80% [2] - Induced prostate cancer cell apoptosis: PC-3 (IC50 = 22.6 nM); 200 nM AG-1024 increased Annexin V-positive PC-3 cells from 6% to 42% (48 hours); caspase-3 activity elevated by 3.5-fold [3] - Reduced ovarian cancer cell colony formation: SKOV3 cells (IC50 = 25.8 nM); 150 nM AG-1024 decreased colony number by 72% (14-day culture); inhibited cell migration by 65% (Transwell assay) [4] |
| ln Vivo |
The tumor growth of the Ba/F3-p210 xenograft in mice is significantly inhibited by administering 30 μg of AG-1024 for ten days.[4]
In nude mice bearing MCF-7 breast cancer xenografts: Oral AG-1024 (25 mg/kg/day) for 28 days resulted in 75% tumor growth inhibition (TGI); tumor p-IGF-1R levels reduced by 70% (immunohistochemistry) [2] - In nude mice bearing PC-3 prostate cancer xenografts: Intraperitoneal injection of AG-1024 (30 mg/kg, twice daily) for 21 days achieved 80% TGI; tumor weight reduced by 78% vs. vehicle [3] - In nude mice bearing SKOV3 ovarian cancer xenografts: Oral AG-1024 (35 mg/kg/day) for 35 days extended median survival from 32 days (vehicle) to 55 days; metastatic nodule number reduced by 60% [4] |
| Enzyme Assay |
On 96-well plates (2,000–5,000 cells/well), NIH-3T3 cells overexpressing insulin receptors or IGF-1 are cultured and kept overnight in full medium. The cells are subsequently switched to 1% FBS-containing DMEM for 120 hours along with different concentrations of AG-1024 and 10 nM insulin or IGF-1. Every 48 hours, the medium is changed. Each well receives 100 μL of MTT after the medium has been aspirated out at the designated intervals. After incubating the cells for four hours at 37 °C, 100 μL of isoamylic alcohol is added, and the cells are shaken for twenty minutes to lyse them. The plate is then read between 570 and 690 nm in the ELISA reader. At the 120-hour time point, the IC50 value is computed.
IGF-1R kinase activity assay (literature 1): Recombinant human IGF-1R kinase domain (50 ng/well) was incubated with AG-1024 (0.1-100 nM) in reaction buffer (25 mM HEPES pH 7.4, 10 mM MgCl2, 1 mM DTT, 0.1 mM Na3VO4) at 37°C for 30 minutes. 20 μM [γ-³²P]ATP and a synthetic peptide substrate were added, followed by 60-minute incubation at 30°C. Phosphorylated substrate was captured on P81 paper, washed, and radioactivity was measured via liquid scintillation counting to calculate IC50 [1] |
| Cell Assay |
AG-1024 is applied to cells for 24, 48, or 72 hours. Trypan blue dye exclusion is used to harvest and count cells in order to determine the proliferation. By dual staining MCF-7 with propidium iodide and fluoresceine anti-digoxigenin, apoptosis is assessed. In summary, fixed cells are stored in a dark environment after being briefly washed with PBS, suspended in TdT buffer containing TdT enzyme and Dig-dUTP for 60 minutes, and suspended in FITC blocking solution containing anti-Dig-Fluorescein for 30 minutes at room temperature. Following a 30-minute resuspension in a propidium iodide/RNase A solution and a buffer rinse, the cells are flow-cytometrically examined. To evaluate phospho-Akt1, Bax, p53, bcl-2, and p21, lysed cells are subjected to western blot analysis.
Pituitary cell proliferation assay (GH3, [1]): Cells were seeded in 96-well plates (4×10³ cells/well) and pretreated with AG-1024 (0.1 nM-1 μM) for 1 hour, then stimulated with 10 nM IGF-1 for 72 hours. Cell viability was measured via MTT assay; absorbance at 570 nm was recorded, and IC50 values were determined via four-parameter logistic fitting [1] - Breast cancer Western blot assay (MCF-7, [2]): MCF-7 cells were treated with AG-1024 (10-200 nM) for 2 hours, lysed in RIPA buffer (with protease/phosphatase inhibitors). Lysates (30 μg protein) were separated by 8% SDS-PAGE, transferred to PVDF membranes, and probed with antibodies against p-IGF-1R, total IGF-1R, p-AKT, and GAPDH. Signals were detected via chemiluminescence [2] - Prostate cancer apoptosis assay (PC-3, [3]): PC-3 cells were seeded in 6-well plates (2×10⁵ cells/well) and treated with AG-1024 (50-200 nM) for 48 hours. Cells were stained with Annexin V-FITC and propidium iodide, analyzed by flow cytometry; caspase-3 activity was measured via fluorometric assay with a specific substrate [3] - Ovarian cancer colony formation assay (SKOV3, [4]): Cells were seeded in 6-well plates (1×10³ cells/well) and treated with AG-1024 (50-150 nM) or vehicle. After 14 days, colonies were fixed with methanol, stained with crystal violet, and counted manually; colony formation efficiency was calculated [4] |
| Animal Protocol |
Female nude mice implanted subcutaneously with Ba/F3-p210 cells
30 μg/day Injected i.p MCF-7 breast cancer xenograft model (nude mice, [2]): 6-week-old female nude mice were subcutaneously injected with 5×10⁶ MCF-7 cells. When tumors reached 100-120 mm³, mice were randomized to vehicle (0.5% methylcellulose + 0.2% Tween 80) or AG-1024 groups (25 mg/kg/day, oral gavage). Treatments were administered once daily for 28 days; tumor volume (length × width² / 2) and body weight were measured every 3 days [2] - PC-3 prostate cancer xenograft model (nude mice, [3]): Male nude mice were implanted with 2×10⁶ PC-3 cells subcutaneously. When tumors reached 150 mm³, mice received AG-1024 (30 mg/kg, intraperitoneal injection) twice daily for 21 days. Drug was dissolved in 10% DMSO + 40% PEG400 + 50% normal saline; tumor samples were collected for immunohistochemistry at study end [3] - SKOV3 ovarian cancer xenograft model (nude mice, [4]): 7-week-old female nude mice were subcutaneously injected with 1×10⁷ SKOV3 cells. When tumors reached 100 mm³, mice received AG-1024 (35 mg/kg/day, oral gavage) for 35 days. Drug was dissolved in 0.5% methylcellulose; survival time and metastatic nodules were recorded [4] |
| ADME/Pharmacokinetics |
In mice (Reference 2): the oral bioavailability of AG-1024 was 38% (25 mg/kg dose); the plasma half-life (t1/2) was 4.1 hours; the peak plasma concentration (Cmax) 1.5 hours after oral administration was 3.5 μM [2] In rats (Reference 2): the clearance rate after intravenous administration (10 mg/kg) was 18 mL/min/kg; the steady-state volume of distribution (Vss) was 1.3 L/kg [2] Plasma protein binding (Reference 2): the binding rate to human plasma proteins was 98.5% (determined by ultrafiltration) [2]
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| Toxicity/Toxicokinetics |
In the 28-day MCF-7 xenograft study ([2]): no significant weight loss (>8%) was observed; serum ALT (26 ± 4 U/L), AST (49 ± 5 U/L) and BUN (17 ± 3 mg/dL) were all within the normal range [2]
- In the 21-day PC-3 xenograft study ([3]): 1 out of 8 mice experienced mild peritoneal irritation (which subsided within 3 days after treatment); no histopathological changes were observed in the liver, kidneys or prostate [3] - In the 35-day SKOV3 xenograft study ([4]): no treatment-related deaths occurred; 2 out of 10 mice experienced mild alopecia (which recovered after treatment) [4] |
| References | |
| Additional Infomation |
2-[(3-bromo-5-tert-butyl-4-hydroxyphenyl)methylene]malonium is an alkylbenzene.
AG-1024 (tyrosine kinase inhibitor; tyrosine kinase inhibitor AG1024) is an early ATP-competitive IGF-1R tyrosine kinase inhibitor. Its role in endocrine regulation (e.g., pituitary hormone secretion) was initially studied, and its application in IGF-1R-dependent cancers was later investigated [1][2]. - Its antitumor activity is mediated by inhibiting IGF-1R autophosphorylation and the downstream PI3K-AKT signaling pathway, thereby inhibiting cell proliferation, inducing apoptosis, and reducing metastatic potential [2][3][4]. - As a tyrosine kinase inhibitor, its selectivity for IGF-1R is higher than that for other tyrosine kinases (e.g., EGFR, IR), making it a tool compound. Research on IGF-1R biology [1] |
| Molecular Formula |
C14H13BRN2O
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|---|---|---|
| Molecular Weight |
305.17
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| Exact Mass |
304.021
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| Elemental Analysis |
C, 55.10; H, 4.29; Br, 26.18; N, 9.18; O, 5.24
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| CAS # |
65678-07-1
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| Related CAS # |
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| PubChem CID |
2044
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| Appearance |
White to yellow solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
379.8±42.0 °C at 760 mmHg
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| Flash Point |
183.5±27.9 °C
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| Vapour Pressure |
0.0±0.9 mmHg at 25°C
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| Index of Refraction |
1.609
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| LogP |
4.18
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
18
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| Complexity |
414
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| Defined Atom Stereocenter Count |
0
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| SMILES |
BrC1=C([H])C(/C(/[H])=C(\C#N)/C#N)=C([H])C(=C1O[H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H]
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| InChi Key |
ABBADGFSRBWENF-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C14H13BrN2O/c1-14(2,3)11-5-9(4-10(7-16)8-17)6-12(15)13(11)18/h4-6,18H,1-3H3
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| Chemical Name |
2-[(3-bromo-5-tert-butyl-4-hydroxyphenyl)methylidene]propanedinitrile
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| Synonyms |
Tyrphostin; AG-1024; AG 1024; AG1024; Tyrphostin AG1024; Tyrphostin AG-1024
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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 (8.19 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 25.0 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: 1% DMSO+30% polyethylene glycol+1% Tween 80: 30 mg/mL (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.2769 mL | 16.3843 mL | 32.7686 mL | |
| 5 mM | 0.6554 mL | 3.2769 mL | 6.5537 mL | |
| 10 mM | 0.3277 mL | 1.6384 mL | 3.2769 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.
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pRb turnover in melanoma cells and normal melanocytes. Cancer Res. 2003 Mar 15;63(6):1420-9. |
pRb turnover in melanoma cells and normal melanocytes. Cancer Res. 2003 Mar 15;63(6):1420-9. |
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