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Purity: ≥98%
T-3775440 (T3775440) HCl is a novel, potent, selective, and irreversible lysine-specific histone demethylase (LSD1) inhibitor with anticancer activity. It inhibits LSD1 with an IC50 value of 2.1 nM. Dysregulation of lysine (K)-specific demethylase 1A (LSD1), also known as KDM1A, has been implicated in the development of various cancers, including leukemia. T-3775440 treatment enforced transdifferentiation of erythroid/megakaryocytic lineages into granulomonocytic-like lineage cells. Mechanistically, T-3775440 disrupted the interaction between LSD1 and growth factor-independent 1B (GFI1B), a transcription factor critical for the differentiation processes of erythroid and megakaryocytic lineage cells. Knockdown of LSD1 and GFI1B recapitulated T-3775440-induced transdifferentiation and cell growth suppression, highlighting the significance of LSD1-GFI1B axis inhibition with regard to the anti-AML effects of T-3775440. Moreover, T-3775440 exhibited significant antitumor efficacy in AEL and AMKL xenograft models. These findings provide a rationale for evaluating LSD1 inhibitors as potential treatments and indicate a novel mechanism of action against AML, particularly AEL and AMKL.
| ln Vitro |
Recombinant human LSD1 is irreversibly inhibited by T-3775440, with a kinact/KI value of 1.7×105 (sec−1 M−1). With an IC50 value of 2.1 nM, T-3775440 exhibits remarkable selectivity for LSD1 in comparison to other monoamine oxidases like MAO-A and MAO-B. Multiple cell line growth is inhibited by T-3775440 as early as day 3 of therapy. Interestingly, T-3775440 therapy frequently increased the granulocyte/macrophage markers CD86 and CD11b on TF-1a and HEL92.1.7 cells, whereas it decreased the erythrocyte markers CD235a and CD71. While just a slight increase in cell surface CD86 expression was seen, T-3775440 also dramatically elevated CD86 mRNA expression in CMK11-5 cells in a concentration-dependent manner. Treatment with T-3775440 breaks the connection between LSD1 and GFI1B in a concentration-dependent way. T-3775440 raises the amounts of dimethylated H3K4 at PI16 and decreases LSD1 binding, but not GFI1B binding [1].
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| ln Vivo |
A single oral dose of 3 to 30 mg/kg of T-3775440 causes dose-dependent upregulation of CD86 mRNA expression in HEL92.1.7 cell tumor xenografts. Direct biomarker testing of PI16 expression levels was done to investigate the targeting effect of this drug in malignancies. Predictably, therapy with T-3775440 markedly reversed the inhibition of PI16. With dosages of 20 and 40 mg/kg, respectively, T-3775440 demonstrated a ~0% 15-day T/C value, indicating a strong anticancer activity in a TF-1a (AEL) tumor xenograft model. The additive AEL model of HEL 92.1.7 and the AMKL model of CMK11-5 had strong anticancer effects in T-3775440 as well, leading to nearly total suppression of tumor development throughout dosage. A mechanism-based side effect of LSD1 inhibition is thought to be responsible for the study's findings, which showed that T-3775440 therapy in mice caused a brief drop in platelets followed by a notable rebound. Body weight differences between vehicle and T-3775440-treated tumor xenograft model mice were statistically significant at the higher dose in a dosing regimen of 5 days on and 2 days off. Nonetheless, all subcutaneous tumor xenograft models showed tolerability of effective T-3775440 dosages [1].
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| References |
[1]. Ishikawa Y, et al. A Novel LSD1 Inhibitor T-3775440 Disrupts GFI1B-Containing Complex Leading to Transdifferentiation and Impaired Growth of AML Cells. Mol Cancer Ther. 2017 Feb;16(2):273-284
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| Molecular Formula |
C18H23CLN4O
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| Molecular Weight |
346.854422807693
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| CAS # |
1422535-52-1
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| Related CAS # |
1422620-34-5;1422535-52-1 (HCl);
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| SMILES |
O=C(C1=CN(C)N=C1)NC2=CC=C([C@H]3[C@H](NCC4CC4)C3)C=C2.[H]Cl
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| InChi Key |
XYFPAGOQZFSLFH-MCJVGQIASA-N
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| InChi Code |
InChI=1S/C18H22N4O.ClH/c1-22-11-14(10-20-22)18(23)21-15-6-4-13(5-7-15)16-8-17(16)19-9-12-2-3-12;/h4-7,10-12,16-17,19H,2-3,8-9H2,1H3,(H,21,23);1H/t16-,17+;/m0./s1
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| Chemical Name |
N-(4-((1S,2R)-2-((Cyclopropylmethyl)amino)cyclopropyl)phenyl)-1-methyl-1H-pyrazole-4-carboxamide hydrochloride
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| Synonyms |
T3775440 HCl; T-3775440 HCl; T 3775440 HCl; T-3775440 Hydrochloride;
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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 : ≥ 30.18 mg/mL (~87.01 mM)
H2O : ~8.33 mg/mL (~24.02 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (7.21 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% 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 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (7.21 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 25.0 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (7.21 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.8831 mL | 14.4155 mL | 28.8309 mL | |
| 5 mM | 0.5766 mL | 2.8831 mL | 5.7662 mL | |
| 10 mM | 0.2883 mL | 1.4415 mL | 2.8831 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.
 T-3775440 leads to cell growth inhibition in AML cell lines.
T-3775440 exhibits significant antileukemic effectsin vivo.Mol Cancer Ther. 2017 Feb;16(2):273-284. |
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 Treatment with T-3775440 induces features of morphologic differentiation in cultured AML cells.
T-3775440 disrupts the LSD1–GFI1B–CoREST complex.Mol Cancer Ther. 2017 Feb;16(2):273-284. |
 Myeloid gene expression correlates with and is required for the growth-inhibitory activity of T-3775440.
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