S2116 是 N-烷基化的反式环丙胺 (TCP) 衍生物，是一种有效的赖氨酸特异性脱甲基酶 1 (LSD1) 抑制剂。S2116 在超级增强子区域增加 H3K9 甲基化和相应的 H3K27 脱乙酰化。S2116 抑制 NOTCH3 和 TAL1 基因的转录，从而诱导 TCP 抵抗性急性淋巴细胞白血病 T-ALL 细胞凋亡 (apoptosis)。S2116 显着延迟异种移植小鼠中 T-ALL 细胞的生长。
| 生物活性 | S2116, a N-alkylated tranylcypromine (TCP) derivative, is a potentlysine-specific demethylase 1 (LSD1)inhibitor. S2116 increases H3K9 methylation and reciprocal H3K27 deacetylation at super-enhancer regions. S2116 inducesapoptosisin TCP-resistant T-cell acute lymphoblastic leukemia (T-ALL) cells by repressing transcription of the NOTCH3 and TAL1 genes. S2116 significantly retardes the growth of T-ALL cells in xenotransplanted mice[1]. |
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体外研究
(In Vitro) | S2116 is particularly effective for T-ALL cell lines with the IC50values between 1.1 μM for human T-ALL cell lines CEM and 6.8 μM for MOLT4[1].
S2116 (4-20 μM; 72 hours) modestly inhibits mitogen-activated normal T-lymphocytes[1].
S2116 (4-8 μM; 24 hours) induces apoptosis and down-regulates the expression of NOTCH3 and TAL1 proteins in T-ALL cells[1].
Cell Viability Assay[1] | Cell Line: | Normal T-lymphocytes | | Concentration: | 4, 8, 12, 16, 20 μM | | Incubation Time: | For 72 hours | | Result: | Modestly inhibited mitogen-activated normal T-lymphocytes. |
Apoptosis Analysis[1] | Cell Line: | T-cell acute lymphoblastic leukemia (T-ALL) cells | | Concentration: | 4, 6, 8 μM | | Incubation Time: | For 24 hours | | Result: | Induced apoptosis, as evidenced by increased annexin-V reactivity on flow cytometry in T-ALL cells in a dose- and time-dependent manner without affecting cell cycle distribution. |
Western Blot Analysis[1] | Cell Line: | T-ALL cells | | Concentration: | 4, 6, 8 μM | | Incubation Time: | For 24 hours | | Result: | Down-regulated the expression of NOTCH3 and TAL1 proteins in T-ALL cells. |
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体内研究
(In Vivo) | S2116 (50 mg/kg; IP; 3 times a week; for 28 days) causes the size of subcutaneous tumors reduced to less than 20% of that in the untreated control[1].
S2116 (50 mg/kg; IP) has a T1/2of 3.76 hours, a Cmaxof 12.7 μM and an AUC of 59.2 μMoh[1].
| Animal Model: | Nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice with MOLT4 cells[1] | | Dosage: | 50 mg/kg | | Administration: | IP; 3 times a week; for 28 days | | Result: | The size of subcutaneous tumors reduced to less than 20% of that in the untreated control. |
| Animal Model: | 8-week-old ICR mice[1] | | Dosage: | 50 mg/kg (Pharmacokinetic Analysis) | | Administration: | IP | | Result: | Had a T1/2of 3.76 hours, a Cmaxof 12.7 μM and an AUC of 59.2 μMoh. |
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| 运输条件 | Room temperature in continental US; may vary elsewhere. |
| 储存方式 | 4°C, sealed storage, away from moisture *In solvent : -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture) |
