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| Targets |
TST-A (Thailanstatin A) specifically targets the spliceosome complex, with high affinity for the SF3B1 subunit of the U2 snRNP complex—a key component of pre-mRNA splicing machinery.
- In vitro pre-mRNA splicing inhibition IC50 = 0.9 nM (HeLa cell nuclear extract assay)[3] - Antiproliferative EC50 in cancer cell lines: 0.1-5 nM (varies by cell type)[1][3] |
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| ln Vitro |
The natural product Thailanstatin A (TST-A) is a strong antiproliferative that is derived from Burkholderia thailandensis MSMB43[2].
With GI50s in the single nM range (1.11-2.69 nM), thailanstatin A (DU-145, NCI-H232A, MDA-MB-231, and SKOV-3 cells) demonstrates strong antiproliferative activities[3].
Pre-mRNA Splicing Inhibition: TST-A (Thailanstatin A) potently blocked pre-mRNA splicing in HeLa cell nuclear extracts and intact cells. At 1 nM, it inhibited splicing of β-globin and CD44 pre-mRNA by >90%, leading to accumulation of unspliced pre-mRNA and aberrant splice products[2][3] - Broad-Spectrum Antiproliferative Activity: Exhibited potent cytotoxicity against diverse human cancer cell lines, including breast (MCF-7, EC50 = 0.3 nM), lung (A549, EC50 = 0.5 nM), colon (HCT116, EC50 = 0.7 nM), and hematological cancers (Jurkat, EC50 = 0.1 nM). Weak activity against normal human fibroblasts (EC50 > 100 nM)[1][3] - Apoptosis Induction: In MCF-7 cells, 1 nM TST-A (Thailanstatin A) induced apoptosis in 55% of cells within 48 hours (Annexin V/PI staining). Western blot showed upregulation of cleaved caspase-3/7 and PARP, and downregulation of anti-apoptotic Bcl-2[1][3] - Spliceosome Targeting Specificity: Did not inhibit other RNA processing events (e.g., transcription, translation) at concentrations up to 10 nM, confirming selectivity for pre-mRNA splicing[3] - ADC Payload Efficacy: When conjugated to anti-HER2 or anti-CD22 antibodies as an ADC payload, TST-A (Thailanstatin A) retained cytotoxicity (EC50 = 0.8-2.3 nM) in antigen-positive cancer cells, with no activity in antigen-negative cells[1] |
| ln Vivo |
Antitumor Efficacy of TST-A-ADC Conjugates: Nude mice bearing HER2-positive NCI-N87 gastric cancer xenografts were treated with anti-HER2-TST-A ADC (1-5 mg/kg, intravenous injection every 3 days for 4 cycles). At 3 mg/kg, tumor growth was inhibited by 82% compared to vehicle controls, with complete tumor regression in 30% of mice[1]
- Efficacy in Hematological Tumor Model: Mice bearing CD22-positive Raji lymphoma xenografts received anti-CD22-TST-A ADC (2-8 mg/kg, intravenous injection every 4 days for 3 cycles). The 5 mg/kg dose reduced tumor weight by 75% and prolonged median survival by 40%[1] - Tolerability: No significant body weight loss (<5%) or organ toxicity (histopathological analysis of liver, kidney, heart) was observed at effective doses (1-5 mg/kg ADC)[1] |
| Enzyme Assay |
In Vitro Pre-mRNA Splicing Assay: HeLa cell nuclear extracts were prepared and mixed with a radiolabeled β-globin pre-mRNA substrate. TST-A (Thailanstatin A) (0.01-10 nM) was added to the reaction mixture, which was incubated at 30°C for 90 minutes. Spliced products (mature mRNA, lariat intron) and unspliced pre-mRNA were separated by denaturing polyacrylamide gel electrophoresis and visualized via autoradiography. The IC50 for splicing inhibition was calculated from dose-response curves[2][3]
- SF3B1 Binding Assay: Purified recombinant SF3B1 protein was immobilized on a sensor chip. TST-A (Thailanstatin A) (0.1-50 nM) was injected at a constant flow rate, and binding affinity was measured via surface plasmon resonance (SPR). A KD value of ~0.5 nM was determined, confirming direct binding to SF3B1[3] |
| Cell Assay |
Antiproliferative Assay: Cancer cells (MCF-7, A549, HCT116, Jurkat) and normal fibroblasts were seeded in 96-well plates (5×103 cells/well) and treated with TST-A (Thailanstatin A) (0.001-100 nM) for 72 hours. Cell viability was assessed via MTT assay, and EC50 values were derived from dose-response curves[1][3]
- Pre-mRNA Splicing Analysis in Intact Cells: HeLa cells were treated with TST-A (Thailanstatin A) (0.1-5 nM) for 24 hours. Total RNA was extracted, and RT-PCR was performed using primers specific for β-globin or CD44 pre-mRNA and mature mRNA. Agarose gel electrophoresis was used to separate unspliced pre-mRNA, aberrant splice variants, and mature mRNA, with band intensity quantified via densitometry[2][3] - Apoptosis Assay: MCF-7 cells were treated with TST-A (Thailanstatin A) (0.1-5 nM) for 48 hours. Cells were stained with Annexin V-FITC and PI, then analyzed by flow cytometry to quantify apoptotic (Annexin V-positive) cells. Western blot was used to detect cleaved caspase-3, cleaved PARP, and Bcl-2 expression[1][3] - ADC Cytotoxicity Assay: Antigen-positive (HER2+ NCI-N87, CD22+ Raji) and antigen-negative (HER2- MDA-MB-231) cells were seeded in 96-well plates. Anti-HER2-TST-A or anti-CD22-TST-A ADC (0.01-50 nM) was added, and cells were incubated for 72 hours. Cell viability was measured via CCK-8 assay, and EC50 values were calculated[1] |
| Animal Protocol |
Solid Tumor Xenograft Model (ADC Efficacy): Female BALB/c-nu mice (4-6 weeks old, 18-22 g) were subcutaneously inoculated with 5×106 NCI-N87 (HER2+) cells. When tumors reached 100-150 mm³, mice were randomly divided into groups (n=6/group): 1) Vehicle control (10% DMSO + 90% saline); 2) Anti-HER2-TST-A ADC (1, 3, 5 mg/kg). ADC was administered via intravenous injection every 3 days for 4 cycles. Tumor volume was measured every 2 days, and mice were euthanized on day 28 for tumor weight and histopathological analysis[1]
- Hematological Tumor Xenograft Model (ADC Efficacy): Mice were intravenously inoculated with 2×106 Raji (CD22+) cells. Treatment was initiated 7 days post-inoculation with anti-CD22-TST-A ADC (2, 5, 8 mg/kg) via intravenous injection every 4 days for 3 cycles. Survival was monitored daily for 42 days, and tumor burden was assessed via bioluminescence imaging (for luciferase-expressing Raji cells)[1] - Toxicity Assessment: Mice from efficacy studies were monitored for body weight changes every 3 days. At study end, major organs (liver, kidney, heart, lung, spleen) were collected, fixed in formalin, and stained with H&E for histopathological examination to evaluate organ toxicity[1] |
| Toxicity/Toxicokinetics |
In vitro cytotoxicity: Low toxicity to normal human fibroblasts (EC50 > 100 nM), with a therapeutic index (EC50 of cancer cells/EC50 of normal cells) of 200-1000 [1][3] - In vivo tolerability: At effective doses (1-5 mg/kg), mice did not show significant weight loss, hematological abnormalities (white blood cells, red blood cells, platelets) or changes in liver and kidney function (ALT, AST, BUN, creatinine) [1] - Plasma protein binding rate: As determined by ultrafiltration, it has a high plasma protein binding rate (97-99%) in human plasma [1]
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| References |
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| Additional Infomation |
Thai Stantin A is a C-glycosyl compound.
It has been reported that Thai Stantin A exists in Burkholderia thailandensis, and there is relevant data. Background: TST-A (Thai Stantin A) is a natural product isolated from Burkholderia thailandensis MSMB43, belonging to the Thai Stantin family of spliceosome inhibitors [3]. -Mechanism of action: It binds to the SF3B1 subunit of the U2 snRNP complex, disrupting the recognition of the 3' splice site in the precursor mRNA. This leads to the accumulation of unspliced precursor mRNA and aberrant splice products, ultimately inducing cell cycle arrest and apoptosis in cancer cells [2][3]. -Therapeutic applications: It has been developed as a payload for antibody-drug conjugates (ADCs) targeting cancer-specific antigens (e.g., HER2, CD22). Antibody-drug conjugates (ADCs) utilize the potent cytotoxicity and tumor-specific delivery of TST-A to minimize off-target effects [1] - Structure-activity relationship: The 10-membered macrolide core and oxazoline moiety are crucial for SF3B1 binding and splice inhibition. Methyl ester modification (TST-A methyl ester) preserves the activity (splice inhibition IC50 = 1.2 nM) [2] - Indications: Intended for the treatment of HER2+ or CD22+ cancers, including gastric cancer, breast cancer, and non-Hodgkin lymphoma, through ADC-based targeted therapy [1] |
| Molecular Formula |
C28H41NO9
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|---|---|
| Molecular Weight |
535.6264
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| Exact Mass |
535.28
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| Elemental Analysis |
C, 62.79; H, 7.72; N, 2.62; O, 26.88
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| CAS # |
1426953-21-0
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| PubChem CID |
71665768
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| Appearance |
White to off-white solid powder
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| LogP |
1.9
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
11
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| Heavy Atom Count |
38
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| Complexity |
960
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| Defined Atom Stereocenter Count |
9
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| SMILES |
C[C@H]1C[C@H]([C@H](O[C@H]1C/C=C(\C)/C=C/[C@@H]2[C@H]([C@@]3(C[C@H](O2)CC(=O)O)CO3)O)C)NC(=O)/C=C\[C@H](C)OC(=O)C
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| InChi Key |
GJKQDOMCDFJANR-FUDLAKRJSA-N
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| InChi Code |
InChI=1S/C28H41NO9/c1-16(7-10-24-27(34)28(15-35-28)14-21(38-24)13-26(32)33)6-9-23-17(2)12-22(19(4)37-23)29-25(31)11-8-18(3)36-20(5)30/h6-8,10-11,17-19,21-24,27,34H,9,12-15H2,1-5H3,(H,29,31)(H,32,33)/b10-7+,11-8-,16-6+/t17-,18-,19+,21+,22+,23-,24+,27+,28+/m0/s1
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| Chemical Name |
2-[(3R,4R,5R,7S)-5-[(1E,3E)-5-[(2S,3S,5R,6R)-5-[[(Z,4S)-4-acetyloxypent-2-enoyl]amino]-3,6-dimethyloxan-2-yl]-3-methylpenta-1,3-dienyl]-4-hydroxy-1,6-dioxaspiro[2.5]octan-7-yl]acetic acid
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| Synonyms |
Thailanstatin A, TST-A;
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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 (~466.74 mM）
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.88 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 (3.88 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 | 1.8670 mL | 9.3348 mL | 18.6696 mL | |
| 5 mM | 0.3734 mL | 1.8670 mL | 3.7339 mL | |
| 10 mM | 0.1867 mL | 0.9335 mL | 1.8670 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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