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S2116 Sale

目录号 : GC64303

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。

S2116 Chemical Structure

Cas No.:2262489-89-2

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5 mg
¥6,750.00
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10 mg
¥10,800.00
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产品描述

S2116, a N-alkylated tranylcypromine (TCP) derivative, is a potent lysine-specific demethylase 1 (LSD1) inhibitor. S2116 increases H3K9 methylation and reciprocal H3K27 deacetylation at super-enhancer regions. S2116 induces apoptosis in 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].

S2116 is particularly effective for T-ALL cell lines with the IC50 values 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].

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 T1/2 of 3.76 hours, a Cmax of 12.7 μM and an AUC of 59.2 μM•h[1].

[1]. Shiori Saito, et al. Eradication of Central Nervous System Leukemia of T-Cell Origin With a Brain-Permeable LSD1 Inhibitor. Clin Cancer Res. 2019 Mar 1;25(5):1601-1611.

Chemical Properties

Cas No. 2262489-89-2 SDF Download SDF
分子式 C22H26ClF2N3O2 分子量 437.91
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1 mM 2.2836 mL 11.4179 mL 22.8357 mL
5 mM 0.4567 mL 2.2836 mL 4.5671 mL
10 mM 0.2284 mL 1.1418 mL 2.2836 mL
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Research Update

Development and Structural Evaluation of N-Alkylated trans-2-Phenylcyclopropylamine-Based LSD1 Inhibitors

ChemMedChem 2020 May 6;15(9):787-793.PMID:32166890DOI:10.1002/cmdc.202000014.

Lysine-specific demethylase 1 (LSD1) is a flavin adenine dinucleotide (FAD)-dependent enzyme that catalyzes the demethylation of histone H3 and regulates gene expression. Because it is implicated in the regulation of diseases such as acute myeloid leukemia, potent LSD1-specific inhibitors have been pursued. Trans-2-phenylcyclopropylamine (2-PCPA)-based inhibitors featuring substitutions on the amino group have emerged, with sub-micromolar affinities toward LSD1 and high selectivities over monoamine oxidases (MAOs). We synthesized two N-alkylated 2-PCPA-based LSD1 inhibitors, S2116 and S2157, based on the previously developed S2101. S2116 and S2157 exhibited enhanced potency for LSD1 by 2.0- to 2.6-fold, as compared with S2101. In addition, they exhibited improved selectivity over MAOs. Structural analyses of LSD1 co-crystallized with S2101, S2116, S2157, or another N-alkylated inhibitor (FCPA-MPE) confirmed that the N-substituents enhance the potency of a 2-PCPA-based inhibitor of LSD1, without constituting the adduct formed with FAD.

Eradication of Central Nervous System Leukemia of T-Cell Origin with a Brain-Permeable LSD1 Inhibitor

Clin Cancer Res 2019 Mar 1;25(5):1601-1611.PMID:30518632DOI:10.1158/1078-0432.CCR-18-0919.

Purpose: Lysine-specific demethylase 1 (LSD1) regulates several biological processes via the bifunctional modulation of enhancer functions. Recently, we reported that LSD1 overexpression is a founder abnormality of T-cell leukemogenesis and is maintained in fully transformed T-cell acute lymphoblastic leukemia (T-ALL) cells. On the basis of this finding, we attempted to develop novel LSD1 inhibitors effective for T-ALL with central nervous system (CNS) involvement. Experimental design: We chemically modified the prototype LSD inhibitor tranylcypromine (TCP) and screened for cytotoxicity against TCP-resistant T-ALL cell lines. In vivo efficacy of novel LSD1 inhibitors was examined in immunodeficient mice transplanted with luciferase-expressing T-ALL cell lines, which faithfully reproduce human T-ALL with CNS involvement. Results: We found robust cytotoxicity against T-ALL cells, but not normal bone marrow progenitors, for two N-alkylated TCP derivatives, S2116 and S2157. The two compounds induced apoptosis in TCP-resistant T-ALL cells in vitro and in vivo by repressing transcription of the NOTCH3 and TAL1 genes through increased H3K9 methylation and reciprocal H3K27 deacetylation at superenhancer regions. Both S2116 and S2157 significantly retarded the growth of T-ALL cells in xenotransplanted mice and prolonged the survival of recipients as monotherapy and in combination with dexamethasone. Notably, S2157 could almost completely eradicate CNS leukemia because of its ability to efficiently pass through the blood-brain barrier. Conclusions: These findings provide a molecular basis and rationale for the inclusion of a brain-permeable LSD1 inhibitor, S2157, in treatment strategies for T-ALL with CNS involvement.