SP2509

SP2509 (1423715-09-6) is a potent (IC50 = 13 nM) and reversible inhibitor of the histone demethylase LSD1 (KDM1A).1 It is inactive against the closely related flavin enzymes MAO A,B as well as lactate dehydrogenase, several CYP’s and hERG. LSD1 regulates the balance between self-renewal and differentiation of stem cells and is highly expressed in various cancers.2-6 SP2509 promotes autophagy in neuroblastoma cells.7

SP 2509 reduces the effect of the LSD1 binding to CoREST, resulting in increased methylation of H3K4 and driving increased expression of p21, p27 and CCAAT/enhancer binding protein α in acute myeloid leukemia cells. Anti-leukemia agent.

A cell-permeable, lysine-specific demethylase 1 (LSD1) active site-targeting phenethylidene-benzohydrazide that inhibits LSD1 activity (IC₅₀ = 13 nM) in a reversible and substrate non-competitive (K_i = 34 nM) manner, while inhibiting CYP3A4 only at much higher concentrations (IC₅₀ = 2.61 μM) and displaying little or no potency towards CYP1A2/2C9/2C19/2D6. MAO-A/B, D-lactate dehydrogenase, glucose oxidase, and hERG (IC₅₀ ≥8.0 μM). Shown to enhance histone H3 Lys9 dimethylation (H3K9me2) in androgen-dependent prostate cancer VCaP cultures (1 to 10 μM) and effectively inhibits LSD1-dependent cancer growth (IC₅₀ in nM = 329/SK-N-MC, 356/AN3 Ca, 429/HT29, 468/MIA PaCa-2, 489/BT-20, 612/HER218, 614/HCT 116, 637/MCF-7, 649/T-47D; 96 h).

Cell permeable: yes

KDM1/LSD1

[1] VENKATASWAMY SORNA. High-Throughput Virtual Screening Identifies Novel N′-(1-Phenylethylidene)-benzohydrazides as Potent, Specific, and Reversible LSD1 Inhibitors[J]. Journal of Medicinal Chemistry, 2013, 56 23: 9496-9508. DOI:10.1021/jm400870h
[2] AMIR HOSSEINI  Saverio M. A comprehensive review of lysine-specific demethylase 1 and its roles in cancer.[J]. Epigenomics, 2017, 9 8: 1123-1142. DOI:10.2217/epi-2017-0022
[3] W FISKUS. Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells[J]. Leukemia, 2014, 28 11: 2155-2164. DOI:10.1038/leu.2014.119
[4] SHIJUN WEN . Novel combination of histone methylation modulators with therapeutic synergy against acute myeloid leukemia in vitro and in vivo[J]. Cancer letters, 2018, 413: Pages 35-45. DOI:10.1016/j.canlet.2017.10.015
[5] CHIA-LUNG TSAI. Stress-induced phosphoprotein 1 acts as a scaffold protein for glycogen synthase kinase-3 beta-mediated phosphorylation of lysine-specific demethylase 1.[J]. Oncogenesis, 2018: 31. DOI:10.1038/s41389-018-0040-z
[6] YUHONG LU. Hypoxia Promotes Resistance to EGFR Inhibition in NSCLC Cells via the Histone Demethylases, LSD1 and PLU-1.[J]. ACS Applied Energy Materials, 2018: 1458-1469. DOI:10.1158/1541-7786.mcr-17-0637
[7] S AMBROSIO. Lysine-specific demethylase LSD1 regulates autophagy in neuroblastoma through SESN2-dependent pathway[J]. Oncogene, 2017, 36 48: 6701-6711. DOI:10.1038/onc.2017.267