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| Targets |
It targets the ATPase activity of SMARCA4 and SMARCA2, which are essential for the function of the SWI/SNF complex. By blocking the ATP-dependent chromatin remodeling activity of these proteins, FHT-1204 disrupts gene expression programs essential for cancer cell proliferation.
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| ln Vitro |
FHT-1204 demonstrates potent inhibition of SMARCA4 and SMARCA2 ATPases with IC50 values of ≤10 nM for both targets. It shows high selectivity over other related ATPases. The potency is confirmed in biochemical ATPase assays using recombinant BRG1 and BRM proteins with acetylated histone peptide substrates (e.g., H4K5acK8acK12ac).
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| ln Vivo |
No specific in vivo activity data is available. Based on its mechanism, in vivo studies likely involve the use of xenograft models derived from SMARCA4-mutant cancers (e.g., non-small cell lung cancer or ovarian cancer) to evaluate anti-tumor efficacy. Oral administration is plausible given its small molecule nature.
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| Enzyme Assay |
For a cell-free biochemical assay, recombinant SMARCA4 (BRG1) or SMARCA2 (BRM) protein (0.5 nM) is incubated with various concentrations of FHT-1204 (0.1-100 nM) in an ATPase assay buffer (20 mM HEPES pH 7.5, 5 mM MgCl2, 1 mM DTT, 0.01% Triton X-100) and 1-10 uM ATP. The reaction proceeds for 60-90 minutes, and the amount of free phosphate released is detected using a Malachite Green-based detection system. The IC50 is calculated from the absorbance readings.
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| Cell Assay |
For cellular assays, cancer cell lines with and without SMARCA4 mutations (e.g., A549 vs. control) are treated with FHT-1204 (1 nM - 1 uM) for 5 days. Cell viability is measured using CellTiter-Glo. Apoptosis is assessed by Caspase-Glo 3/7 assay. Chromatin accessibility changes are measured using ATAC-seq or by monitoring BRG1/BRM occupancy via ChIP-qPCR at specific gene loci.
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| Animal Protocol |
For in vivo efficacy studies, female nude mice are subcutaneously implanted with SMARCA4-mutated human tumor xenografts (e.g., NCI-H1299). When tumors reach ~150-200 mm3, mice are randomized and treated orally (PO) or intraperitoneally (IP) with FHT-1204 daily at doses of 10-50 mg/kg. Tumor volumes are measured biweekly for up to 4 weeks. Plasma exposure levels are determined via LC-MS/MS to confirm pharmacokinetic exposure.
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| ADME/Pharmacokinetics |
FHT-1204 (MW: 525.6) is soluble in DMSO and is stable for up to 3 years as a powder at -20degC and for up to 1 year in solution at -80degC. As a small molecule ATPase inhibitor, it is expected to have reasonable oral bioavailability, though specific PK parameters (T1/2, Cmax, AUC) have not been disclosed.
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| Toxicity/Toxicokinetics |
As a research chemical, specific toxicological data is limited. Standard laboratory safety precautions should be followed. It should be handled with care, as with any compound that has potent cellular activity. Eye and skin protection are recommended. It is not for human use.
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| References | |
| Additional Infomation |
FHT-1204 is a potent, selective, and orally bioavailable inhibitor of SMARCA4/SMARCA2 ATPases (BRG1 and BRM) with IC50s of ≤10 nM (WO2020160180A1; compound 70).
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| Molecular Formula |
C24H23N5O5S2
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|---|---|
| Molecular Weight |
525.60
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| Exact Mass |
525.114
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| CAS # |
2468048-24-8
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| PubChem CID |
154667935
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| Appearance |
Off-white to light brown solid powder
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| LogP |
2
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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 |
9
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| Heavy Atom Count |
36
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| Complexity |
863
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| Defined Atom Stereocenter Count |
1
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| SMILES |
N1(S(C)(=O)=O)C=CC(C(N[C@@H](COC)C(=O)NC2=NC(C3=CC=CC(C4C=CN=CC=4)=C3)=CS2)=O)=C1
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| InChi Key |
AXMLAOCXALIIRY-FQEVSTJZSA-N
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| InChi Code |
InChI=1S/C24H23N5O5S2/c1-34-14-20(26-22(30)19-8-11-29(13-19)36(2,32)33)23(31)28-24-27-21(15-35-24)18-5-3-4-17(12-18)16-6-9-25-10-7-16/h3-13,15,20H,14H2,1-2H3,(H,26,30)(H,27,28,31)/t20-/m0/s1
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| Chemical Name |
N-[(2S)-3-methoxy-1-oxo-1-[[4-(3-pyridin-4-ylphenyl)-1,3-thiazol-2-yl]amino]propan-2-yl]-1-methylsulfonylpyrrole-3-carboxamide
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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 : ~25 mg/mL (~47.56 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 | 1.9026 mL | 9.5129 mL | 19.0259 mL | |
| 5 mM | 0.3805 mL | 1.9026 mL | 3.8052 mL | |
| 10 mM | 0.1903 mL | 0.9513 mL | 1.9026 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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