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

Humans Cell Line, Tumor Histone Demethylases / antagonists & inhibitors N-Myc Proto-Oncogene Protein / genetics Neuroblastoma / drug therapy Benzoates / pharmacology
Bortezomib Epigenetic Lysine-specific demethylase 1 MYCN Neuroblastoma

Journal

European journal of medicinal chemistry
ISSN: 1768-3254
Titre abrégé: Eur J Med Chem
Pays: France
ID NLM: 0420510

Informations de publication

Date de publication:
15 Dec 2022
Historique:
received: 19 08 2022
revised: 27 09 2022
accepted: 29 09 2022
pubmed: 13 10 2022
medline: 22 11 2022
entrez: 12 10 2022
Statut: ppublish

Résumé

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 (IC

Identifiants

DOI: 10.1016/j.ejmech.2022.114818 PMID: 36223680
pubmed: 36223680
pii: S0223-5234(22)00720-6
doi: 10.1016/j.ejmech.2022.114818
pii:
doi:

Substances chimiques

Histone Demethylases EC 1.14.11.-
MYCN protein, human 0
N-Myc Proto-Oncogene Protein 0
Benzoates 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

114818

Informations de copyright

Copyright © 2022 Elsevier Masson SAS. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Patrick M. Woster reports financial support was provided by National Institutes of Health. Patrick M. Woster has patent #PCT/US2020/036028 pending to Medical University of South Carolina.

Auteurs

Catherine M Mills (CM)

Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, 70 President St, Charleston, SC, 29425, USA.

Jonathan Turner (J)

Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, 70 President St, Charleston, SC, 29425, USA.

Ivett C Piña (IC)

Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, 70 President St, Charleston, SC, 29425, USA.

Kathleen A Garrabrant (KA)

Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, 70 President St, Charleston, SC, 29425, USA.

Dirk Geerts (D)

Glycostem Therapeutics, Kloosterstraat 9, 5349 AB, Oss, the Netherlands.

André S Bachmann (AS)

Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI, 49503, USA.

Yuri K Peterson (YK)

Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, 70 President St, Charleston, SC, 29425, USA.

Patrick M Woster (PM)

Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, 70 President St, Charleston, SC, 29425, USA. Electronic address: woster@musc.edu.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Synthesis and evaluation of small molecule...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Synthesis and evaluation of small molecule...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Oxidoreductases › Oxidoreductases acting on CH-NH group donors › Oxidoreductases, (N-demethylating) › Histone Demethylases › Synthesis and evaluation of small molecule...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs de transcription à motif basique et à glissière à leucines › Facteurs de transcription à motifs basiques hélice-boucle-hélice et à glissière à leucines › Protéine du proto-oncogène N-Myc › Synthesis and evaluation of small molecule...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs du tissu nerveux › Tumeurs neuroectodermiques › Tumeurs neuroépitheliales › Tumeurs neuroectodermiques primitives › Tumeurs neuroectodermiques primitives périphériques › Neuroblastome › Synthesis and evaluation of small molecule...
questionsmedicales.fr › Composés chimiques organiques › Hydrocarbures › Hydrocarbures cycliques › Hydrocarbures aromatiques › Dérivés du benzène › Benzoates › Synthesis and evaluation of small molecule...