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| Targets |
FHD-286 targets BRG1 (SMARCA4) and BRM (SMARCA2), the catalytic ATPase subunits of the SWI/SNF chromatin remodeling complex. It acts as an inhibitor, blocking the ATPase activity of these proteins. By inhibiting BRG1/BRM, FHD-286 disrupts chromatin remodeling and gene expression programs that are essential for the survival of certain cancer cells, including those in AML.
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| ln Vitro |
FHD-286 (10 to 100 nM) causes evaporation of cells for 7 days, ending MLL rearrangement (r), mutation (mt) NPM1 chromosome and 3q26 damage (EVI1 overexpression). FHD-286 also resulted in transcription of ATAC-Seq peaks and genome-wide consensus, as well as site-specific mRNA expression determined by RNA-Seq. These findings were linked to significant reductions in the target genome of MYC, mTORC1, E2F, interferon-γ, IL6 -JAK-STAT3, as well as inflammatory response and oxidative phosphorylation genes. The results of QPCR analysis showed a substantial decrease in the mRNA expression of the SPI1, BCL2, and MYC genes. A log2-fold reduction is observed in [1]. Mass spectrometry investigation of the lumen of FHD-286-treated AML cells revealed c-Myc, SPI1, MEF2C, KMT2C, and CDK4 (in MOLM13) and EVI1, c-Myb, CDK6, and c-Myc (in AML191) cells.
In vitro, FHD-286 is a potent inhibitor of BRG1/BRM ATPase activity. It shows anti-proliferative effects in cancer cell lines dependent on BRG1/BRM function. The compound is the first SMARCA2/SMARCA4 dual inhibitor. Specific IC50 values are not provided in the available sources. |
| ln Vivo |
In vivo, FHD-286 reduces tumor burden and increases survival in patient-derived xenograft (PDX) mouse models of AML when used alone or in combination with venetoclax. The compound is orally active. These data support its potential for the treatment of AML and other BAF-related disorders.
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| Enzyme Assay |
The in vitro enzyme assay for FHD-286 involves measuring the inhibition of BRG1/BRM ATPase activity. Recombinant BRG1 or BRM proteins are incubated with ATP in the presence of varying compound concentrations. The ATPase activity is quantified by measuring the release of inorganic phosphate using colorimetric assays.
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| Cell Assay |
Cellular assays are performed using AML cell lines or other cancer cell lines dependent on BRG1/BRM function. Cells are treated with FHD-286 at various concentrations, and cell viability is assessed using assays such as MTT or CellTiter-Glo. Chromatin remodeling and gene expression changes are assessed by Western blotting and RNA-seq.
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| Animal Protocol |
Animal/Disease Models: B16F10 tumor-bearing mice [2]
Doses: 1.5 mg/kg Route of Administration: oral; FHD-286 (1.5 mg/kg; diaphragm) causes increased levels of FNγ and th1-type chemokine CXCL10 [2]. Results lasting 10 days: increased levels of IFNγ and Th1 chemokine CXCL10. In vivo animal studies are conducted in patient-derived xenograft (PDX) mouse models of AML. FHD-286 is administered orally. Tumor burden is measured, and survival is monitored. The compound is also evaluated in combination with venetoclax. |
| ADME/Pharmacokinetics |
FHD-286 is an orally active compound. It is being developed for the treatment of AML and other BAF-related disorders. Specific PK parameters such as half-life, bioavailability, and clearance are not detailed in the available sources.
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| Toxicity/Toxicokinetics |
Toxicity data for FHD-286 are not reported in the available sources. As an investigational compound, it is used for research purposes only.
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| References |
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| Additional Infomation |
Camibirstat is an orally bioavailable small allosteric transcription activator BRG1 (SWI/SNF-associated matrix-associated actin-dependent chromatin regulator A subfamily member 4; SMARCA4) and BRM (SWI/SNF-associated matrix-associated actin-dependent chromatin regulator A subfamily member 2; SMARCA2) inhibitor with potential antitumor activity. After oral administration, Camibirstat targets and binds to and inhibits the activity of BRG1 and/or BRM. BRG1 and BRM are major ATPase components of the BRG1/BRM-associated factor (BAF) complex and are mutually exclusive subunits. This may lead to inhibition of the SWI/SNF chromatin remodeling complex, disrupting chromatin remodeling and gene expression, thereby downregulating oncogenic pathways and inhibiting tumor cell proliferation. BAF is an important regulator of transcriptional programs and gene expression. Mutations in BAF or its transcription factor chaperones are associated with certain diseases, including cancer.
FHD-286 is a research compound being investigated for the treatment of BAF-related disorders, including acute myeloid leukemia. It is the first SMARCA2/SMARCA4 dual inhibitor and is orally active. The compound is available from chemical suppliers for research use only. |
| Molecular Formula |
C24H30N6O6S2
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|---|---|
| Molecular Weight |
562.66
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| Exact Mass |
562.166
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| CAS # |
2671128-05-3
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| PubChem CID |
156818030
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
1.3
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
38
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| Complexity |
926
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| Defined Atom Stereocenter Count |
3
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| SMILES |
[C@H]1(C)O[C@@H](C)CN(C2=NC(C3N=C(NC(=O)[C@@H](NC(=O)C4=CN(S(=O)(C)=O)C=C4)COC)SC=3)=CC=C2)C1
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| InChi Key |
JBLQNFBXKOAIHG-FCEWJHQRSA-N
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| InChi Code |
InChI=1S/C24H30N6O6S2/c1-15-10-29(11-16(2)36-15)21-7-5-6-18(25-21)20-14-37-24(27-20)28-23(32)19(13-35-3)26-22(31)17-8-9-30(12-17)38(4,33)34/h5-9,12,14-16,19H,10-11,13H2,1-4H3,(H,26,31)(H,27,28,32)/t15-,16+,19-/m0/s1
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| Chemical Name |
N-[(2S)-1-[[4-[6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyridin-2-yl]-1,3-thiazol-2-yl]amino]-3-methoxy-1-oxopropan-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 : ~250 mg/mL (~444.32 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.70 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 20.8 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 2: ≥ 2.08 mg/mL (3.70 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7773 mL | 8.8864 mL | 17.7727 mL | |
| 5 mM | 0.3555 mL | 1.7773 mL | 3.5545 mL | |
| 10 mM | 0.1777 mL | 0.8886 mL | 1.7773 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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