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

GSK2879552 reduces the characteristics of stem cells, causes the differentiation of cells resistant to sorafenib, and inhibits the activity of KDM1A histone demethylase. In cells resistant to sorafenib, GSK2879552 downregulates β-catenin signaling activity and suppresses the transcription of Wnt antagonists [1].

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1. In sorafenib-resistant hepatocellular carcinoma (HCC) stem-like cells: GSK2879552 dramatically suppresses the stem-like properties of sorafenib-resistant HCC cells. Mechanistically, it derepresses the expression of multiple upstream negative regulators of the Wnt signaling pathway, thereby downregulating the β-catenin pathway. Additionally, GSK2879552 resensitizes sorafenib-resistant HCC cells to sorafenib in vitro [1]
2. In various tumor cell lines: A proliferation screen of multiple tumor cell lines shows that small cell lung carcinoma (SCLC) is sensitive to LSD1 inhibition by GSK2879552. The subset of SCLC cell lines and primary samples that exhibit growth inhibition upon treatment with GSK2879552 display DNA hypomethylation of a signature set of probes, which is proposed as a predictive biomarker of its antitumor activity [2]

In mice containing SCLC xenografts, GSK2879552 (1.5 mg/kg, po) therapy showed tumor growth reduction [2].

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1. In sorafenib-resistant HCC xenograft models: GSK2879552 resensitizes sorafenib-resistant HCC cells to sorafenib in vivo, at least in part by reducing the cancer stem cell (CSC) pool, thereby enhancing the therapeutic efficacy of sorafenib [1]

Cell Proliferation Assay[2].
Cell Types: 9/28 small cell lung carcinoma (SCLC) lines and 20/29 AML lines.
Tested Concentrations: 0-10000 nM.
Incubation Duration: 6 days.
Experimental Results: Inhibited cell proliferation.

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RT-PCR [1].
Cell Types: Resistant HCC cells (PLC/PRF/5 and Huh7).
Tested Concentrations: 0, 1, 2 μM.
Incubation Duration: 24 h.
Experimental Results: Displayed decreased mRNA expression levels of stem cell markers, such as Lgr5, Sox9, Nanog and CD90, and elevated mRNA expression levels of differentiation markers Alb and Hnf4.

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1. Sorafenib-resistant HCC stem-like cell assay: Sorafenib-resistant HCC cells with stem-like properties are cultured in appropriate medium. GSK2879552 is added to the culture system at specific concentrations. After a certain period of incubation, the stem-like properties of the cells are evaluated through relevant assays (e.g., detection of stem cell markers, sphere-forming capacity). Meanwhile, the expression levels of upstream negative regulators of the Wnt signaling pathway and β-catenin are analyzed by molecular biology techniques to verify the mechanism of action [1]
2. Tumor cell proliferation assay: Various tumor cell lines (including SCLC cell lines) are seeded in culture plates and cultured until adherent. GSK2879552 is added at gradient concentrations, with a vehicle control group set up. After incubation for a specified time, cell proliferation is detected using appropriate methods (e.g., CCK-8 assay, colony formation assay) to determine the sensitivity of different tumor cell lines to GSK2879552. For SCLC cells, DNA methylation status of the signature probes is detected to analyze the correlation with drug sensitivity [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 piperidine compound in which the 1 and 4 positions of the piperidine ring are substituted with (4-carboxyphenyl)methyl and {[(1R,2S)-2-phenylcyclopropyl]amino}methyl, respectively. It is a potent and irreversible inhibitor of lysine-specific demethylase 1 (LSD1, also known as KDM1A). This compound has been clinically studied for the treatment of acute myeloid leukemia and small cell lung cancer. It is an EC 1.14.99.66 (lysine-specific histone demethylase 1A) inhibitor and an antitumor drug. It belongs to the benzoic acid, monocarboxylic acid, piperidine, cyclopropane, tertiary amine, secondary amine, and benzene compounds.
The LSD1 inhibitor GSK2879552 is an orally potent and irreversible inhibitor of lysine-specific demethylase 1 (LSD1) with potential antitumor activity. After administration, GSK2879552 binds to LSD1 and inhibits its activity. LSD1 is a demethylase that inhibits the expression of target genes by converting the dimethylated form of histone H3 lysine 4 (H3K4) to monomethylated and unmethylated H3K4. LSD1 inhibition can enhance H3K4 methylation and increase the expression of tumor suppressor genes. This may lead to the inhibition of the growth of LSD1-overexpressing tumor cells. LSD1 is overexpressed in some tumor cells and 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 class of compounds. It is a potent, selective, and mechanism-based irreversible LSD1 inactivator [2]
2. Therapeutic potential in hepatocellular carcinoma (HCC): GSK2879552 can improve the therapeutic effect of sorafenib by targeting KDM1A to alleviate acquired resistance to sorafenib in HCC patients. Its mechanism of action is related to the regulation of the Wnt/β-catenin signaling pathway and the clearance of sorafenib-resistant stem cell-like cells [1]
3. Therapeutic potential in small cell lung cancer: Small cell lung cancer is sensitive to GSK2879552, and its DNA hypomethylation characteristics can be used as a biomarker to predict its anti-tumor activity in small cell lung cancer, providing a basis for precision treatment of small cell lung cancer [2]

C23H30CL2N2O2

437.4025

364.215

1401966-69-5

GSK2879552 dihydrochloride;1902123-72-1

66571643

White to off-white solid powder

4.071

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)

Solubility in Formulation 1: ≥ 2.75 mg/mL (7.54 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 27.5 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.

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Solubility in Formulation 2: ≥ 2.75 mg/mL (7.54 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 27.5 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.

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Solubility in Formulation 3: ≥ 2.75 mg/mL (7.54 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 27.5 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)