GSK2879552

GSK2879552 is an orally available, irreversible inhibitor of lysine specific demethylase 1 (LSD1), with potential antineoplastic activity.

Signaling Pathways >> Epigenetics >> Histone Demethylase

Research Areas >> Cancer

GSK2879552 inhibits KDM1A histone demethylase activity, inducing differentiation of sorafenib-resistant cells and attenuates stemness properties. GSK2879552 derepresses the transcription of Wnt antagonists and downregulates β-catenin signaling activity in sorafenib-resistant cells[1]. GSK2879552 is 280-fold selective over D-amino acid oxidase, allowing for direct comparison of inactivation efficiency (KIapp=520 ± 170 μM, kinact=0.12 ± 0.01 min−1, kinact/KIapp=2.3×10-4 ± 1.31×10-5 min-1 μM-1). GSK2879552 inhibits the growth of 9/28 small cell lung carcinoma (SCLC) lines and 20/29 AML lines, with EC50 of 2-240 nM[2].

GSK2879552 (1.5 mg/kg, p.o.) treatment exhibits tumor growth inhibition in SCLC xenograft bearing mice. There is 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 demonstrate partial TGI (38% and 49% respectively) in response to GSK2879552, while no significant TGI is observed for SHP77 bearing mice[2].

Viable cells are measured in Cell Counting Kit-8 (CCK8) assay. Briefly, cells are cultured in a 96-well plate overnight at a density of 5×103 cells per well and treated with the indicated concentrations of sorafenib (0 μM, 40 μM or 80 μM) for 24 h. Subsequently, the cells are incubated with 10 μL CCK8 for 60 min at 37°C, 5% CO2. The absorbance of optical density at 450 nm (A450) is determined with Varioskan Flash.

[1]. Huang M, et al. 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]. Mohammad HP, et al. A DNA Hypomethylation Signature Predicts Antitumor Activity of LSD1 Inhibitors in SCLC. Cancer Cell. 2015 Jul 13;28(1):57-69.

GSK-J4 | QC6352 | SP-2509 | CPI-455 | trans-2-Phenylcyclopropylamine hemisulfate salt | 5-Carboxy-8-hydroxyquinoline | ML324 | GSK-LSD1 Dihydrochloride | NCGC00244536 | Daminozide | ORY-1001(trans) | JIB-04 | AS 8351 | KDM5-IN-1 | KDM5A-IN-1