Synthesis and evaluation of small molecule inhibitors of LSD1 for use against MYCN-expressing neuroblastoma

The epigenetic regulator lysine specific demethylase 1 (LSD1), a MYCN cofactor, cooperatively silences MYCN suppressor genes. Furthermore, LSD1 has been correlated with adverse effects in neuroblastic tumors by propagating an undifferentiated, malignant phenotype. We observed that high LSD1 mRNA expression in MYCN-expressing neuroblastoma (NB) correlated with poor prognosis, implicating LSD1 as an oncogenic accomplice in high-grade NB. Thus, LSD1 inhibition is a potential strategy for targeting treatment-resistant MYCN-expressing NB. Tranylcypromine-based covalent LSD1 inhibitors have demonstrated anti-tumor activity but are associated with undesirable off-target effects, such that only 2 non-covalent LSD1 inhibitors are in clinical trials. We now report 3 novel scaffolds for reversible LSD1 inhibition: 2-(arylsulfonamido)benzoic acid, N-(2-(1H-tetrazol-5-yl)phenyl)benzenesulfonamide and 2-(arylcarboxamido)benzoic acid analogues. The most active of these analogues, compound 48, exhibited potent and selective mixed reversible inhibition of LSD1 (IC50 = 0.58 μM) and significantly increased global H3K4me2 in NB cells. In addition, combination treatment with 48 and bortezomib in NB cells results in a synergistic effect. [Display omitted] •High LSD1 expression in MYCN-expressing neuroblastoma leads to reduced survival.•In silico analysis led to identification of 3 new scaffolds for LSD1 inhibitor design.•The most active reversible LSD1 inhibitor was compound 48 (IC50 0.58 μM).•Compound 48 was selective for LSD1 and increased cellular H3K4me2 in vitro.•48 at 100 nM in combination with bortezomib was synergistic in 2 neuroblastoma lines.