Lysine-specific histone demethylase 1A (KDM1A, also known as LSD1) [1]
Lysine-specific histone demethylase 1A (KDM1A, also known as LSD1) [2]

GSK2879552降低干细胞的特性，导致对索拉非尼耐药的细胞分化，并抑制KDM1A组蛋白去甲基化酶的活性。在对索拉非尼耐药的细胞中，GSK2879552 下调 β-连环蛋白信号活性并抑制 Wnt 拮抗剂的转录 [1]。

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1. 在索拉非尼耐药的肝细胞癌（HCC）干细胞样细胞中的作用：GSK2879552可显著抑制索拉非尼耐药HCC干细胞样细胞的干细胞特性。其作用机制为解除Wnt信号通路多个上游负调控因子的表达抑制，进而下调β-连环蛋白通路。此外，GSK2879552可在体外使索拉非尼耐药的HCC细胞重新对索拉非尼敏感[1]
2. 在多种肿瘤细胞系中的作用：对多种肿瘤细胞系进行增殖筛选发现，小细胞肺癌（SCLC）细胞对GSK2879552介导的LSD1抑制敏感。经GSK2879552处理后表现出增殖抑制的SCLC细胞系和原发样本，均存在特征性探针的DNA低甲基化现象，该低甲基化特征可作为其抗肿瘤活性的预测生物标志物[2]

在含有 SCLC 异种移植物的小鼠中，GSK2879552（1.5 mg/kg，口服）治疗显示肿瘤生长减少 [2]。

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1. 在索拉非尼耐药HCC异种移植模型中的作用：GSK2879552在体内可使索拉非尼耐药的HCC细胞重新对索拉非尼敏感，这一效果至少部分是通过减少癌症干细胞（CSC）池实现的，从而增强索拉非尼的治疗效果[1]

细胞增殖测定[2]。
细胞类型：9/28 小细胞肺癌 (SCLC) 系和 20/29 AML 系。
测试浓度：0-10000 nM。
孵化持续时间：6天。
实验结果：抑制细胞增殖。

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RT-PCR [1]。
细胞类型：耐药 HCC 细胞（PLC/PRF/5 和 Huh7）。
测试浓度：0、1、2 μM。
孵化持续时间：24小时。
实验结果：显示干细胞标志物（如Lgr5、Sox9、Nanog和CD90）的mRNA表达水平降低，而分化标志物Alb和Hnf4的mRNA表达水平升高。

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1. 索拉非尼耐药HCC干细胞样细胞实验：将具有干细胞样特性的索拉非尼耐药HCC细胞在适宜培养基中培养，向培养体系中加入特定浓度的GSK2879552。孵育一定时间后，通过相关实验（如干细胞标志物检测、成球能力检测等）评估细胞的干细胞特性；同时采用分子生物学技术分析Wnt信号通路上游负调控因子及β-连环蛋白的表达水平，验证其作用机制[1]
2. 肿瘤细胞增殖实验：将多种肿瘤细胞系（包括SCLC细胞系）接种到培养板中，培养至贴壁后，加入梯度浓度的GSK2879552，并设置溶媒对照组。孵育指定时间后，采用适宜方法（如CCK-8法、克隆形成实验等）检测细胞增殖情况，明确不同肿瘤细胞系对GSK2879552的敏感性；对SCLC细胞，检测特征性探针的DNA甲基化状态，分析其与药物敏感性的相关性[2]

Animal/Disease Models: NCI-H526 and NCI-H1417 xenografts[2].
Doses: 1.5 mg/kg.
Route of Administration: PO daily for 25-35 days.
Experimental Results: There was 57% and 83% tumor growth inhibition (TGI) in NCI- H526 and NCI-H1417 tumor bearing mice respectively. NCI-H510 and NCI-H69 tumor bearing mice also demonstrated partial TGI (38% and 49% respectively) in response to GSK2879552, while no significant TGI was observed for SHP77 bearing mice.

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1. Sorafenib-resistant HCC xenograft model assay: Male nude mice are used to establish xenograft models by inoculating sorafenib-resistant HCC cells subcutaneously or orthotopically. When the tumors reach a certain volume, the mice are randomly divided into groups: control group, sorafenib monotherapy group, GSK2879552 monotherapy group, and GSK2879552 combined with sorafenib group. GSK2879552 is administered via an appropriate route (details not specified in the literature), and sorafenib is given according to standard protocols. Tumor volume and body weight of mice are measured regularly. At the end of the experiment, tumors are harvested to detect the CSC pool size and the expression of Wnt/β-catenin pathway-related proteins [1]

[1]. Targeting KDM1A attenuates Wnt/β-catenin signaling pathway to eliminate sorafenib-resistant stem-like cells in hepatocellular carcinoma. Cancer Lett. 2017 Apr 2;398:12-21.

[2]. A DNA Hypomethylation Signature Predicts Antitumor Activity of LSD1 Inhibitors in SCLC. Cancer Cell. 2015 Jul 13;28(1):57-69.

GSK2879552 is a member of the class of piperidines that is piperidine substituted by (4-carboxyphenyl)methyl and {[(1R,2S)-2-phenylcyclopropyl]amino}methyl groups at positions 1 and 4, respectively. It is a potent and irreversible inhibitor of lysine specific demethylase 1 (LSD1, also known as KDM1A). It was under clinical investigation for the treatment of acute myeloid leukaemia and small cell lung carcinoma. It has a role as an EC 1.14.99.66 (lysine-specific histone demethylase 1A) inhibitor and an antineoplastic agent. It is a member of benzoic acids, a monocarboxylic acid, a member of piperidines, a member of cyclopropanes, a tertiary amino compound, a secondary amino compound and a member of benzenes.
LSD1 Inhibitor GSK2879552 is an orally available, irreversible, inhibitor of lysine specific demethylase 1 (LSD1), with potential antineoplastic activity. Upon administration, GSK2879552 binds to and inhibits LSD1, a demethylase that suppresses the expression of target genes by converting the dimethylated form of lysine at position 4 of histone H3 (H3K4) to mono- and unmethylated H3K4. LSD1 inhibition enhances H3K4 methylation and increases the expression of tumor-suppressor genes. This may lead to an inhibition of cell growth in LSD1-overexpressing tumor cells. LSD1, overexpressed in certain tumor cells, plays a key role in tumor cell growth and survival.

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1. Drug characteristics: GSK2879552 is a KDM1A (LSD1) inhibitor belonging to the cyclopropylamine-containing compound class. It is a potent, selective, and mechanism-based irreversible inactivator of LSD1 [2]
2. Therapeutic potential in HCC: GSK2879552 can alleviate acquired resistance to sorafenib in HCC patients by targeting KDM1A, thereby increasing the therapeutic efficacy of sorafenib. Its mechanism is associated with the regulation of the Wnt/β-catenin signaling pathway and the elimination of sorafenib-resistant stem-like cells [1]
3. Therapeutic potential in SCLC: SCLC is sensitive to GSK2879552, and the DNA hypomethylation signature can be used as a predictive biomarker for its antitumor activity in SCLC, providing a basis for precise treatment of SCLC [2]

C23H30CL2N2O2

437.4025

364.215

1401966-69-5

GSK2879552 dihydrochloride;1902123-72-1

66571643

White to off-white solid powder

4.071

52.57

2

4

7

27

475

2

C1CN(CCC1CN[C@@H]2C[C@H]2C3=CC=CC=C3)CC4=CC=C(C=C4)C(=O)O

LRULVYSBRWUVGR-FCHUYYIVSA-N

InChI=1S/C23H28N2O2/c26-23(27)20-8-6-18(7-9-20)16-25-12-10-17(11-13-25)15-24-22-14-21(22)19-4-2-1-3-5-19/h1-9,17,21-22,24H,10-16H2,(H,26,27)/t21-,22+/m0/s1

4-((4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic acid

GSK-2879552; GSK2879552; GSK 2879552.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~25 mg/mL (~68.59 mM)

配方 1 中的溶解度: ≥ 2.75 mg/mL (7.54 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 27.5 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.75 mg/mL (7.54 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 27.5mg/mL澄清的DMSO储备液加入到900μL 20％SBE-β-CD生理盐水中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.75 mg/mL (7.54 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 27.5 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。