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| Targets |
S116836 targets multiple tyrosine kinases, including BCR-ABL wild-type and the T315I mutant, which is a common cause of imatinib resistance in chronic myelogenous leukemia (CML). By inhibiting BCR-ABL kinase activity, S116836 blocks downstream signaling pathways that promote leukemia cell proliferation and survival. The compound also inhibits the PD-1/PD-L1 interaction, which may enhance anti-tumor immune responses. This dual mechanism makes S116836 a promising candidate for treating imatinib-resistant CML.
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| ln Vitro |
BaF3/WT and BaF3/T315I cells' cell proliferation is considerably reduced by S116836 (0.01-1 μM; 24 hours) (IC50 values: 0.05 μM and 0.20 μM, respectively) [1]. In BaF3/WT cells, S116836 (0.01-1 μM; 24 hours) dramatically reduced the level of p-BCR-ABL expression. In BaF3/WT and BaF3/T315I cells, S116836 (0.01-1 μM; 24 hours) also markedly reduced the expression levels of p-Crk1 and p-STAT5, which are downstream signaling proteins of BCR-ABL [1]. In the G0/G1 phase of the cell cycle, BaF3/WT and BaF3/T315I cells are arrested by S116836 (0.1, 0.3, and 0.5 μM; 24 hours) [1]. In BaF3/WT and BaF3/T315I cells, S116836 (0.3 and 0.5 μM; 24 hours) raises ROS generation and lowers GSH levels [1]. In BaF3/WT and BaF3/T315I cells, S116836 (0.1, 0.3, and 0.5 μM; 24 hours) causes apoptosis [1]. PDGFRα and its downstream signaling components, including STAT3, AKT, and Erk1/2, are efficiently inhibited by S116836. Growth of FIP1L1-PDGFRα-expressing WT and T674I tumor cells is significantly inhibited by S116836 [3].
In vitro, S116836 blocks both wild-type and T315I mutant BCR-ABL with nanomolar potency. It synergistically induces apoptosis in imatinib-resistant chronic myelogenous leukemia cells. The compound's ability to inhibit BCR-ABL kinase activity and induce apoptosis has been confirmed in various cell-based assays. S116836 also inhibits the PD-1/PD-L1 interaction. Its multi-targeted activity makes it a valuable tool for studying imatinib-resistant leukemia. |
| ln Vivo |
S116836 (intraperitoneally administered at 100 or 200 mg/kg to q3d×6 athymic NCR nude mice) decreases the weight and size of xenograft tumors expressing both WT and T315I mutant BCR-ABL [1]. Orally administered for 14 days at a dose of 200 mg/kg/d, S116836 suppresses the development of xenografted T674I-FIP1L1-PDGFRα cells in nude mice [3].
In vivo, S116836 is an orally active tyrosine kinase inhibitor. However, specific in vivo efficacy data in animal models are not extensively detailed in the available literature. The compound's ability to inhibit BCR-ABL and PD-1/PD-L1 suggests potential therapeutic applications in imatinib-resistant CML and other cancers. Further studies would be required to evaluate its therapeutic potential. |
| Enzyme Assay |
In vitro enzyme/receptor binding assays for S116836 are kinase activity assays using purified BCR-ABL kinase (wild-type and T315I mutant). The enzyme is incubated with a peptide substrate and ATP in the presence of varying concentrations of S116836, and the extent of substrate phosphorylation is measured. The IC50 for inhibition of BCR-ABL kinase activity is determined from dose-response curves. PD-1/PD-L1 binding assays can be used to assess the compound's ability to disrupt this protein-protein interaction.
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| Cell Assay |
In vitro cellular assays for S116836 are performed using imatinib-resistant CML cell lines expressing the T315I mutant. Cells are treated with varying concentrations of S116836, and cell viability is measured using MTT assays. Apoptosis is evaluated using annexin V staining and caspase activity assays. BCR-ABL phosphorylation is assessed by Western blotting. PD-1/PD-L1 interaction inhibition is assessed in immune cell assays.
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| Animal Protocol |
In vivo animal experiments for S116836 are conducted in xenograft mouse models of imatinib-resistant CML. Immunocompromised mice are implanted with T315I mutant CML cells and treated with S116836 via oral administration. Tumor growth inhibition is monitored, and endpoints include tumor volume, tumor weight, and survival. Pharmacodynamic markers such as BCR-ABL phosphorylation in tumor tissues are assessed. However, detailed protocols are not extensively documented in the available literature.
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| ADME/Pharmacokinetics |
S116836 has a molecular weight of 502.49 g/mol and a molecular formula of C27H21F3N6O. It is an orally active multi-targeted tyrosine kinase inhibitor. The compound should be stored in a cool, dry place for long-term storage. Detailed pharmacokinetic parameters such as half-life, Cmax, and bioavailability have not been extensively reported.
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| Toxicity/Toxicokinetics |
The toxicological profile of S116836 has not been extensively characterized. As a tyrosine kinase inhibitor, the compound may have potential off-target effects and toxicity to normal cells. No significant toxicity has been reported in the available literature. Standard toxicology studies would be necessary to establish its safety profile. The compound is a research tool and is not intended for human use.
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| References |
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| Additional Infomation |
S116836 is a novel, orally active, multi-targeted tyrosine kinase inhibitor that blocks both wild-type and T315I mutant BCR-ABL with nanomolar potency. It synergistically induces apoptosis in imatinib-resistant chronic myelogenous leukemia cells. S116836 is also a highly selective inhibitor of the PD-1/PD-L1 interaction. It is a research compound with potential applications in imatinib-resistant CML and cancer immunotherapy.
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| Molecular Formula |
C27H21F3N6O
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| Molecular Weight |
502.49
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| Exact Mass |
502.172
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| Elemental Analysis |
C, 64.54; H, 4.21; F, 11.34; N, 16.72; O, 3.18
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| CAS # |
1257628-57-1
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| PubChem CID |
51037409
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| Appearance |
Off-white to yellow solid powder
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| LogP |
4.9
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
37
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| Complexity |
859
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CC1=C(C=C(C=C1)C(=O)NC2=CC(=CC(=C2)C(F)(F)F)N3C=CN=C3)C#CC4=CN=C(N=C4)NC5CC5
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| InChi Key |
DHNAWOULRSDMRU-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C27H21F3N6O/c1-17-2-4-20(10-19(17)5-3-18-14-32-26(33-15-18)35-22-6-7-22)25(37)34-23-11-21(27(28,29)30)12-24(13-23)36-9-8-31-16-36/h2,4,8-16,22H,6-7H2,1H3,(H,34,37)(H,32,33,35)
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| Chemical Name |
3-[2-[2-(cyclopropylamino)pyrimidin-5-yl]ethynyl]-N-[3-imidazol-1-yl-5-(trifluoromethyl)phenyl]-4-methylbenzamide
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| Synonyms |
S 116836; S-116836; S116836
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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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| 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 : ~32 mg/mL (~63.68 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 | 1.9901 mL | 9.9504 mL | 19.9009 mL | |
| 5 mM | 0.3980 mL | 1.9901 mL | 3.9802 mL | |
| 10 mM | 0.1990 mL | 0.9950 mL | 1.9901 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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