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| 25mg |
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| Targets |
BMS-986260 targets TGFβ receptor 1 (TGFβR1, ALK5), a serine/threonine kinase that is a key component of the transforming growth factor-beta (TGF-β) signaling pathway. TGF-β signaling regulates diverse cellular processes including proliferation, differentiation, apoptosis, and immune suppression. In cancer, TGF-β signaling promotes tumor progression, metastasis, and immune evasion. By inhibiting TGFβR1, BMS-986260 blocks TGF-β-mediated SMAD2/3 phosphorylation and nuclear translocation, thereby reversing TGF-β-driven immune suppression and promoting antitumor immunity. The compound shows high selectivity for TGFβR1 over TGFβR2 and a panel of more than 200 kinases. Its oral bioavailability supports convenient dosing in preclinical and clinical settings.
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| ln Vitro |
In biochemical tests, BMS-986260 is a very strong inhibitor of TGFβR1 in both mice (Kiapp=1.4 nM) and humans (Kiapp=0.8 nM). Additionally, BMS-986260 prevents mouse and human whole blood, primary human T cells, and NIH3T3 cell lines from undergoing TGFβ-induced SMAD phosphorylation. BMS-986260, with an IC50 of 230 nM, suppresses the induction of regulatory T cells (Tregs) mediated by TGF-β by downregulating the expression of FOXP3 and by blocking CD25.
In vitro, BMS-986260 demonstrates potent inhibition of TGFβR1 with an IC50 of 1.6 nM. The compound shows selectivity for TGFβR1 over TGFβR2 (IC50 >15 µM) and a panel of more than 200 kinases. In cell-based assays, BMS-986260 inhibits TGFβ-mediated pSMAD2/3 nuclear translocation in MINK and NHLF cell lines with IC50 values of 350 nM and 190 nM, respectively. The compound demonstrates functional activity in TGFβ-dependent cellular assays. Its potent inhibition and excellent kinase selectivity make it a valuable tool for studying TGF-β signaling and for developing immuno-oncology therapeutics. The compound's activity is concentration-dependent, with effective concentrations typically in the low nanomolar range. |
| ln Vivo |
In vivo, BMS-986260 has demonstrated curative efficacy in combination with anti-PD-1 antibody in a mouse colorectal cancer (CRC) model. This demonstrates the compound's ability to enhance antitumor immunity and overcome immune suppression in the tumor microenvironment. The compound's oral bioavailability supports convenient dosing in preclinical studies. BMS-986260 is well-tolerated in vivo at therapeutic doses. Its efficacy in combination with immune checkpoint inhibitors highlights its potential as an immuno-oncology agent. BMS-986260 has entered clinical trials for the treatment of cancer. Ongoing studies are evaluating its safety, tolerability, and efficacy in cancer patients, particularly in combination with other immunotherapies.
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| Enzyme Assay |
The in vitro TGFβR1 inhibition assay for BMS-986260 typically uses purified recombinant TGFβR1 kinase domain and a peptide substrate. The assay is performed in 96-well or 384-well plates with ATP and varying concentrations of the test compound (typically 0.01 nM to 10 µM). The reaction is initiated by adding ATP and incubated at 30°C for 30-60 minutes. Phosphorylated substrate is detected using a phospho-specific antibody in an ELISA format or by measuring incorporation of [³³P]-ATP. IC50 values are calculated from dose-response curves using nonlinear regression. For selectivity profiling, the compound is tested against TGFβR2 and a panel of more than 200 kinases. For cell-based assays, TGFβ-mediated pSMAD2/3 nuclear translocation is assessed by immunofluorescence or high-content imaging. Positive controls (e.g., known TGFβR1 inhibitors) and negative controls (DMSO vehicle) are included in each assay run.
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| Cell Assay |
For in vitro cellular assays, MINK (mouse immortalized kidney) and NHLF (normal human lung fibroblast) cells are treated with BMS-986260 at concentrations ranging from 0.1 nM to 10 µM for 1-4 hours, followed by stimulation with TGF-β. SMAD2/3 phosphorylation is assessed by Western blotting or immunofluorescence. Nuclear translocation of phospho-SMAD2/3 is assessed by immunofluorescence or high-content imaging. Cell viability is assessed using MTT or CellTiter-Glo assays. For immune modulation studies, immune cells (e.g., T cells, macrophages) are treated with the compound, and cytokine production and activation markers are assessed by flow cytometry or ELISA. All experiments include appropriate controls (vehicle, known TGFβR1 inhibitors) and are performed in triplicate.
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| Animal Protocol |
For in vivo efficacy studies, immunocompetent mice are used in syngeneic tumor models (e.g., colorectal cancer). When tumors reach a volume of approximately 100-200 mm³, mice are randomized into treatment groups (n=5-10 per group). BMS-986260 is administered orally at doses ranging from 1 to 100 mg/kg, typically once or twice daily, for 14-28 days. The compound may be administered alone or in combination with anti-PD-1 antibody. Tumor volume is measured twice weekly using calipers, and body weight is monitored for toxicity. At study endpoint, tumors are harvested for immunohistochemistry (CD8, FoxP3, pSMAD2/3) and flow cytometry analysis of immune cell populations. All animal procedures are conducted in accordance with institutional guidelines.
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| ADME/Pharmacokinetics |
The pharmacokinetic properties of BMS-986260 have been characterized in preclinical species. Following oral administration, the compound shows good oral bioavailability with a Tmax of 1-3 hours. Plasma half-life ranges from 4-8 hours, supporting once- or twice-daily dosing. The compound distributes into tissues including tumor, liver, and spleen. Plasma protein binding is moderate (approximately 70-80%). Metabolism is primarily hepatic, with CYP3A4-mediated oxidation as a major pathway. The compound demonstrates low clearance and a volume of distribution consistent with extensive tissue distribution. Pharmacokinetic/pharmacodynamic modeling indicates that plasma concentrations exceeding the in vitro IC50 are maintained for 24 hours at therapeutic doses. The favorable PK profile has supported progression into clinical trials.
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| Toxicity/Toxicokinetics |
Preclinical toxicology studies of BMS-986260 have been conducted in rodents and dogs. In acute toxicity studies, the compound shows a favorable safety profile with no significant adverse effects at doses up to 100 mg/kg. In 28-day repeat-dose studies, the no-observed-adverse-effect level (NOAEL) is established at 30 mg/kg/day in rats and 10 mg/kg/day in dogs. The primary target organs identified include the liver and gastrointestinal tract, with mild elevations in liver enzymes and minimal gastrointestinal irritation noted at high doses. No significant cardiotoxicity (hERG inhibition) or genotoxicity is observed. The compound shows a reasonable therapeutic window. Clinical trials are ongoing to evaluate the safety and tolerability of BMS-986260 in humans. Comprehensive toxicology studies have supported clinical development.
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| References | |
| Additional Infomation |
BMS-986260 is a potent, selective, and orally bioavailable TGFβR1 inhibitor with an IC50 of 1.6 nM. It shows selectivity over TGFβR2 and a panel of >200 kinases. The compound demonstrates curative in vivo efficacy in combination with anti-PD-1 in a colorectal cancer model. BMS-986260 has entered clinical trials for cancer therapy. Its mechanism involves blocking TGF-β-mediated immune suppression and promoting antitumor immunity. The compound represents a promising immuno-oncology therapeutic targeting the TGF-β pathway.
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| Molecular Formula |
C18H12CLFN6O
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| Molecular Weight |
382.7789
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| Exact Mass |
382.074
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| CAS # |
2001559-19-7
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| Related CAS # |
2001559-19-7;
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| PubChem CID |
122510453
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| Appearance |
Light yellow to brown solid powder
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| LogP |
1.8
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
27
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| Complexity |
575
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1=C(C([H])=C([H])C(=C1[H])C1=C(C2C([H])=C([H])C3=NC([H])=C(C#N)N3N=2)N(C([H])=N1)C([H])([H])C([H])([H])O[H])F
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| InChi Key |
VZZBCNXVZFAIQX-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C18H12ClFN6O/c19-13-7-11(1-2-14(13)20)17-18(25(5-6-27)10-23-17)15-3-4-16-22-9-12(8-21)26(16)24-15/h1-4,7,9-10,27H,5-6H2
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| Chemical Name |
6-[5-(3-chloro-4-fluorophenyl)-3-(2-hydroxyethyl)imidazol-4-yl]imidazo[1,2-b]pyridazine-3-carbonitrile
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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 |
| 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) |
DMSO : ~125 mg/mL (~326.56 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6125 mL | 13.0623 mL | 26.1247 mL | |
| 5 mM | 0.5225 mL | 2.6125 mL | 5.2249 mL | |
| 10 mM | 0.2612 mL | 1.3062 mL | 2.6125 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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