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| 5mg |
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| 10mg |
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| Targets |
KDM1/LSD1
GSK2879552 dihydrochloride specifically targets lysine-specific demethylase 1 (LSD1), also known as KDM1A. LSD1 is a histone H3K4me1/2 demethylase found in various transcriptional co-repressor complexes, including histone deacetylases (HDAC1/2) and CoREST. LSD1 is a key regulator of the epigenome that modulates gene expression through post-translational modification of histones and is overexpressed in certain tumor cells. Inhibition of LSD1 enhances H3K4 methylation and increases the expression of tumor-suppressor genes. |
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| ln Vitro |
GSK2879552 dihydrochloride reduces the characteristics of stem cells, causes sorafenib-resistant cells to differentiate, and inhibits KDM1A histone demethylase activity. In sorafenib-resistant cells, GSK2879552 dihydrochloride downregulates β-catenin signaling activity and inhibits Wnt antagonists' transcription [1].
In vitro, GSK2879552 dihydrochloride potently inhibits LSD1/KDM1A histone demethylase activity. The compound reduces stem cell characteristics and induces differentiation of sorafenib-resistant cells. By irreversibly inhibiting LSD1, the compound enhances H3K4 methylation, leading to increased expression of tumor-suppressor genes. These effects result in reduced proliferation and increased differentiation of cancer cells. The compound has demonstrated activity in various cancer cell lines, particularly those with LSD1 overexpression. |
| ln Vivo |
In mice containing SCLC xenografts, GSK2879552 dihydrochloride (1.5 mg/kg, po) therapy showed tumor growth reduction [2].
In vivo, GSK2879552 dihydrochloride has been evaluated in preclinical models and clinical trials. As an orally bioavailable compound, it is administered to patients and animal models via oral route. The compound has shown potential antineoplastic activity in small cell lung cancer, acute myeloid leukemia, and other LSD1-dysregulated malignancies. Clinical trials have investigated its safety and efficacy, though specific phase and outcome data are not detailed in the available literature. |
| Enzyme Assay |
The in vitro LSD1 inhibition assay for GSK2879552 dihydrochloride typically uses recombinant LSD1 enzyme and a histone H3K4me2 peptide substrate. Demethylase activity is measured using fluorescence-based or mass spectrometry-based detection methods. The compound's irreversible inhibition is confirmed by pre-incubation with the enzyme followed by dilution or dialysis to remove unbound compound. IC50 values are calculated from dose-response curves. Selectivity profiling against other FAD-dependent enzymes such as MAO-A and MAO-B is performed using similar assay formats.
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| Cell Assay |
Cell Viability 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. 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. Cellular assays for GSK2879552 dihydrochloride are conducted in cancer cell lines, including small cell lung cancer and acute myeloid leukemia cells. Cells are treated with varying concentrations of the compound for 72-96 hours. Stem cell characteristics are assessed by measuring the expression of stem cell markers and performing functional assays such as colony formation. Differentiation is evaluated by morphological changes and expression of differentiation markers. Cell viability and proliferation are measured using standard assays. |
| Animal Protocol |
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. In vivo studies for GSK2879552 dihydrochloride have been conducted in preclinical mouse models of cancer. The compound is administered orally at doses determined by pharmacokinetic studies. Efficacy is assessed by measuring tumor growth inhibition, survival, and pharmacodynamic markers such as H3K4 methylation levels and tumor-suppressor gene expression. Clinical trials have been conducted in patients with small cell lung cancer, acute myeloid leukemia, and other malignancies, though specific protocols and outcomes are not detailed in the available literature. |
| ADME/Pharmacokinetics |
GSK2879552 dihydrochloride is an orally bioavailable compound with favorable pharmacokinetic properties. It has been evaluated in clinical trials, indicating that its pharmacokinetic profile supports human dosing. The compound has a molecular weight of 437.40 g/mol as the dihydrochloride salt. As a small molecule LSD1 inhibitor, it is expected to have good oral absorption and tissue distribution. Specific PK parameters such as half-life and bioavailability are not detailed in the available literature.
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| Toxicity/Toxicokinetics |
Toxicity data for GSK2879552 dihydrochloride is derived from clinical trials and preclinical studies. As a clinical-stage compound, it has undergone safety evaluation in humans. However, specific toxicity data and adverse event profiles are not detailed in the available literature. As with all investigational drugs, the compound is subject to rigorous safety testing. The compound is for research use only and not for therapeutic use outside of approved clinical trials.
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| References |
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| Additional Infomation |
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 derivatives.
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 at position 4 (H3K4) to monomethylated and unmethylated H3K4. LSD1 inhibition enhances H3K4 methylation and increases the expression of tumor suppressor genes. This may lead to the suppression of the growth of LSD1-overexpressing tumor cells. LSD1 is overexpressed in some tumor cells and plays a crucial role in tumor cell growth and survival. GSK2879552 dihydrochloride is a first-in-class, orally bioavailable, irreversible LSD1 inhibitor that has progressed to clinical trials for small cell lung cancer, acute myeloid leukemia, and other LSD1-dysregulated malignancies. By irreversibly inhibiting LSD1, the compound enhances H3K4 methylation and increases tumor-suppressor gene expression. It reduces stem cell characteristics and induces differentiation of cancer cells. The compound represents a promising therapeutic approach for cancers with LSD1 overexpression. |
| Molecular Formula |
C23H28CL2N2O2
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|---|---|
| Molecular Weight |
435.3866
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| Exact Mass |
364.215
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| CAS # |
1902123-72-1
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| Related CAS # |
GSK2879552;1401966-69-5
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| PubChem CID |
66571643
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| Appearance |
White to off-white solid powder
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| LogP |
1.3
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
27
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| Complexity |
475
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| Defined Atom Stereocenter Count |
2
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| SMILES |
OC(C1C=CC(=CC=1)CN1CCC(CN[C@H]2[C@H](C3C=CC=CC=3)C2)CC1)=O.Cl.Cl
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| InChi Key |
LRULVYSBRWUVGR-FCHUYYIVSA-N
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| InChi Code |
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
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| Chemical Name |
4-[[4-[[[(1R,2S)-2-phenylcyclopropyl]amino]methyl]piperidin-1-yl]methyl]benzoic acid
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| HS Tariff Code |
2934.99.9001
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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, 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) |
H2O : 100 mg/mL (228.62 mM)
DMSO : 31.25 mg/mL (71.44 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.72 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 (5.72 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 (5.72 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 8.33 mg/mL (19.04 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication (<60°C). |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2968 mL | 11.4840 mL | 22.9679 mL | |
| 5 mM | 0.4594 mL | 2.2968 mL | 4.5936 mL | |
| 10 mM | 0.2297 mL | 1.1484 mL | 2.2968 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.
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