2. Academic Validation
  3. Synthesis and evaluation of small molecule inhibitors of LSD1 for use against MYCN-expressing neuroblastoma

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

  • Eur J Med Chem. 2022 Dec 15;244:114818. doi: 10.1016/j.ejmech.2022.114818.
Catherine M Mills 1,  Jonathan Turner 1,  Ivett C Piña 1,  Kathleen A Garrabrant 1,  Dirk Geerts 2,  André S Bachmann 3,  Yuri K Peterson 1,  Patrick M Woster 4
Affiliations

Affiliations

  • 1 Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, 70 President St, Charleston, SC, 29425, USA.
  • 2 Glycostem Therapeutics, Kloosterstraat 9, 5349 AB, Oss, the Netherlands.
  • 3 Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI, 49503, USA.
  • 4 Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, 70 President St, Charleston, SC, 29425, USA. Electronic address: woster@musc.edu.
PMID: 36223680 DOI: 10.1016/j.ejmech.2022.114818
Abstract

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.

Keywords

Bortezomib; Epigenetic; Lysine-specific demethylase 1; MYCN; Neuroblastoma.

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