TAS1440
Based on 1 Customer Validation
TAS1440 is an orally active LSD1/KDM1A inhibitor with a human IC50 of 4.8 nM. TAS1440 non-covalently binds to the histone H3-binding pocket of LSD1, inhibiting demethylase activity and disrupting repressive complexes with INSM1 and SMAD2. TAS1440 activates tumor-suppressive TGF-β and NOTCH signaling pathways via transcriptional reprogramming. TAS1440 can be used for the research of small cell lung cancer, specifically the SCLC-A subtype.
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- Purity : 98.03%
- CAS No.: 2098585-77-2
- 화학식: C28H27F2N3O2
- 분자량:475.53
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보관:Powder -20°C, 3 years , 4°C, 2 years ; In solvent -80°C, 6 months , -20°C, 1 month
To place orders, for customer services and technical support, please contact: MedChemExpress USA
Tel: 609-228-6898 E-mail: [email protected] [email protected]
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Biological Activity
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Chemical Information
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용액&용해도
- Protocol
- 순도&문서
- References
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Help & FAQs
Biological Activity
제품 설명
IC50 & Target
[1]|
KDM1/LSD1 4.8 nM (IC50) |
In Vitro
TAS1440 is a highly selective, histone H3-competitive inhibitor of purified recombinant human LSD1, with an IC50 of 4.8 nM and no significant activity against LSD2, MAO-A, MAO-B, or a broad panel of other epigenetic enzymes[1].
TAS1440 (0-7500 nM; 8 days) selectively inhibits proliferation of SCLC-A cell lines, with the greatest potency in NCI-H1417, NCI-H510A, NCI-H146, and COR-L51 cells, and exhibits stronger antiproliferative activity than covalent LSD1 inhibitors in these sensitive models[1].
TAS1440 (300 nM; 1-7 days) induces transcriptional reprogramming in SCLC cell lines, activating tumor-suppressive TGF-β and NOTCH pathways and suppressing neuroendocrine gene expression, with the most pronounced changes in TAS1440-sensitive SCLC-A cell lines[1].
TAS1440 (300 nM; 30 min-5 days) activates TGF-β and NOTCH signaling in SCLC-A cell lines by inducing SMAD2 phosphorylation, NOTCH1 upregulation, and nuclear accumulation of active pathway components, while also disrupting INSM1-LSD1 and SMAD2-LSD1 protein complexes more effectively than covalent LSD1 inhibitors[1].
TAS1440 (300 nM; 5 days) induces global epigenetic reprogramming in SCLC-A cell lines, increasing active histone marks (H3K4me1, H3K4me2, H3K27ac) at TSSs and promoting INSM1 and SMAD2 binding to tumor-suppressive NOTCH and TGF-β pathway gene promoters[1].
TAS1440 (100-3,000 nM; 7 days) antiproliferative and transcriptional effects in SCLC-A cell lines depend on LSD1 expression and catalytic activity, while its ability to disrupt INSM1/SMAD2-LSD1 complexes is independent of LSD1 catalytic function[1].
TAS1440 (300 nM; 2 h-10 days) requires INSM1 for its antiproliferative effects, transcriptional reprogramming, and activation of TGF-β/NOTCH signaling in SCLC-A cell lines[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only. Further protocols information, click here.
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Cell Line:19 small cell lung cancer (SCLC) cell lines stratified into SCLC-A, SCLC-N, and SCLC-P subtypes
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Concentration:7500 nM
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Incubation Time:8 days
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Result:Showed the strongest growth suppression in SCLC-A cell lines compared to SCLC-N and SCLC-P subtypes.
Exhibited the lowest IC50 values in NCI-H1417, NCI-H510A, NCI-H146, and COR-L51 SCLC-A cells.
Exhibited greater potency than covalent LSD1 inhibitors in sensitive SCLC-A lines, as covalent comparators often had IC50 values ≥1,000 nM or were right-censored at the 7,500 nM testing limit.
Showed broadly similar inhibition patterns to another H3-competitive inhibitor (CC-90011) but greater potency in the most sensitive SCLC-A lines.
In Vivo
TAS1440 (50 mg/kg/day; p.o.; daily; 3 weeks) significantly reduces tumor growth in INSM1-wild-type but not INSM1-knockout NCI-H146 SCLC-A xenografts, demonstrating INSM1 dependence for in vivo efficacy[1].
TAS1440 (50 mg/kg/day; p.o.; daily; 4 weeks) reduces pulmonary tumor burden by 67% in an orthotopic NCI-H146 SCLC-A xenograft model[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:C.B-17 SCID mice (male, 6-week-old, subcutaneously injected with NCI‑H1417, NCI‑H146, NCI‑H510A, COR-L51 and NCI-H146 INSM1-KO cells)[1]
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Dosage:16.7 mg/kg/day; 50 mg/kg/day
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Administration:p.o.; daily; 3 weeks
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Result:Significantly reduced tumor growth in NCI-H1417 xenografts compared with vehicle at 16.7 and 50 mg/kg/day.
Significantly reduced tumor growth in NCI-H146, NCI-H510A, and COR-L51 xenografts compared with vehicle at 50 mg/kg/day.
Upregulated NOTCH1 and increased phosphorylated SMAD2 (pSMAD2) in xenograft tumors.
Induced NOTCH/TGF-β pathway genes (NOTCH1, HES1, TGFB2, TGFBR2, ID3) and reduced ASCL1 and DLL3 in xenograft tumors.
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Animal Model:C.B-17 SCID mice (male, 6-week-old, subcutaneously injected with NCI‑H1417, NCI‑H146, NCI‑H510A, COR-L51 and NCI-H146 INSM1-KO cells)[1]
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Dosage:50 mg/kg/day
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Administration:p.o.; daily; 3 weeks
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Result:Significantly reduced tumor growth in INSM1-wild-type NCI-H146 xenografts compared with vehicle.
Had no significant effect on tumor growth in INSM1-knockout NCI-H146 xenografts.
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Animal Model:C.B-17 SCID mice (male, 6-week-old, subcutaneously injected with NCI‑H1417, NCI‑H146, NCI‑H510A, COR-L51 and NCI-H146 INSM1-KO cells)[1]
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Dosage:50 mg/kg/day
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Administration:p.o.; daily; 4 weeks
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Result:Reduced pulmonary tumor area by 67% compared with vehicle, as measured by micro-CT volumetric quantification.
Clinical Trial
| NCT Number | Sponsor | Condition | Start Date |
Phase
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|---|---|---|---|---|
| NCT01329991 | Plexxikon| | 2011-05 | PHASE1 |
Chemical Information
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CAS No. 2098585-77-2
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Appearance Solid
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분자량 475.53
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화학식 C28H27F2N3O2
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Color White to off-white
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SMILES
N[C@H](C1)CCN1C(C(C=C2C3=CC=C(C#N)C(F)=C3)=CC=C2C4=CC=C(C=C4F)CC(C)(C)O)=O
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선적
Room temperature in continental US; may vary elsewhere.
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보관
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
용액&용해도
In Vitro:
DMSO : 70 mg/mL (147.20 mM; Need ultrasonic; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO)
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
Protocol
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Notch Pathway Solutions
The Notch pathway is a contact-dependent signaling pathway that controls cell-fate decisions, differentiation, proliferation, and tissue patterning through interactions between membrane-bound Notch receptors and membrane-bound ligands on neighboring cells. Canonical Notch signaling is activated when ligand engagement triggers proteolytic release of the Notch intracellular domain, which enters the nucleus and regulates transcription together with DNA-binding transcriptional complexes. In the canonical mechanism, ligand-dependent Notch activation leads to release of the intracellular Notch domain, and presenilin-dependent γ-secretase activity is required for production of the active intracellular signaling fragment. The released intracellular domain functions as a nuclear signal that converts Notch receptor activation at the membrane into transcriptional regulation of target programs such as HES/HEY-family genes and other context-dependent downstream targets. The literature links Notch p
순도&문서
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Data Sheet (280 KB)
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SDS (252 KB)
- English - EN (252 KB)
- Français - FR (252 KB)
- Deutsch - DE (252 KB)
- Norwegian - NO (252 KB)
- Español - ES (252 KB)
- Swedish - SV (252 KB)
- Italian - IT (252 KB)
- Korean - KR (252 KB)
- Portuguese - PT (252 KB)
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Handling Instructions (2659 KB)
References
Complete Stock Solution Preparation Table
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
| Optional Solvent | Concentration Solvent Mass | 1 mg | 5 mg | 10 mg | 25 mg |
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| DMSO | 1 mM | 2.1029 mL | 10.5146 mL | 21.0292 mL | 52.5729 mL |
| 5 mM | 0.4206 mL | 2.1029 mL | 4.2058 mL | 10.5146 mL | |
| 10 mM | 0.2103 mL | 1.0515 mL | 2.1029 mL | 5.2573 mL | |
| 15 mM | 0.1402 mL | 0.7010 mL | 1.4019 mL | 3.5049 mL | |
| 20 mM | 0.1051 mL | 0.5257 mL | 1.0515 mL | 2.6286 mL | |
| 25 mM | 0.0841 mL | 0.4206 mL | 0.8412 mL | 2.1029 mL | |
| 30 mM | 0.0701 mL | 0.3505 mL | 0.7010 mL | 1.7524 mL | |
| 40 mM | 0.0526 mL | 0.2629 mL | 0.5257 mL | 1.3143 mL | |
| 50 mM | 0.0421 mL | 0.2103 mL | 0.4206 mL | 1.0515 mL | |
| 60 mM | 0.0350 mL | 0.1752 mL | 0.3505 mL | 0.8762 mL | |
| 80 mM | 0.0263 mL | 0.1314 mL | 0.2629 mL | 0.6572 mL | |
| 100 mM | 0.0210 mL | 0.1051 mL | 0.2103 mL | 0.5257 mL |
TAS1440 Related Classifications
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