Novel non-covalent LSD1 inhibitors endowed with anticancer effects in leukemia and solid tumor cellular models.

Cell Line, Tumor Cell Proliferation Enzyme Inhibitors / chemistry Histone Demethylases Humans Leukemia / drug therapy
Cancer Drug discovery Histone lysine methyltransferases Lysine-specific demethylase 1 Polypharmacology

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:
05 Jul 2022
Historique:
received: 11 01 2022
revised: 20 04 2022
accepted: 21 04 2022
pubmed: 8 5 2022
medline: 26 5 2022
entrez: 7 5 2022
Statut: ppublish

Résumé

LSD1 is a histone lysine demethylase proposed as therapeutic target in cancer. Chemical modifications applied at C2, C4 and/or C7 positions of the quinazoline core of the previously reported dual LSD1/G9a inhibitor 1 led to a series of non-covalent, highly active, and selective LSD1 inhibitors (2-4 and 6-30) and to the dual LSD1/G9a inhibitor 5 that was more potent than 1 against LSD1. In THP-1 and MV4-11 leukemic cells, the most potent compounds (7, 8, and 29) showed antiproliferative effects at sub-micromolar level without significant toxicity at 1 μM in non-cancer AHH-1 cells. In MV4-11 cells, the new derivatives increased the levels of the LSD1 histone mark H3K4me2 and induced the re-expression of the CD86 gene silenced by LSD1, thereby confirming the inhibition of LSD1 at cellular level. In breast MDA-MB-231 as well as in rhabdomyosarcoma RD and RH30 cells, taken as examples of solid tumors, the same compounds displayed cell growth arrest in the same IC

Identifiants

DOI: 10.1016/j.ejmech.2022.114410 PMID: 35525212
pubmed: 35525212
pii: S0223-5234(22)00312-9
doi: 10.1016/j.ejmech.2022.114410
pii:
doi:

Substances chimiques

Enzyme Inhibitors 0
Histone Demethylases EC 1.14.11.-

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

114410

Informations de copyright

Copyright © 2022 Elsevier Masson SAS. All rights reserved.

Auteurs

Martina Menna (M)

Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185, Rome, Italy.

Francesco Fiorentino (F)

Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185, Rome, Italy.

Biagina Marrocco (B)

Department of Biology and Biotechnology, University of Pavia, Via Ferrata 9, 27100, Pavia, Italy.

Alessia Lucidi (A)

Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185, Rome, Italy.

Stefano Tomassi (S)

Department of Pharmacy, University of Naples "Federico II", via Domenico Montesano 49, 80131, Naples, Italy.

Domenica Cilli (D)

Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, via Adamello 16, 20139, Milan, Italy.

Mauro Romanenghi (M)

Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, via Adamello 16, 20139, Milan, Italy.

Matteo Cassandri (M)

Department of Oncohematology, Bambino Gesù Children's Hospital, IRCCS, viale di San Paolo 15, 00146, Rome, Italy.

Silvia Pomella (S)

Department of Oncohematology, Bambino Gesù Children's Hospital, IRCCS, viale di San Paolo 15, 00146, Rome, Italy.

Michele Pezzella (M)

Department of Oncohematology, Bambino Gesù Children's Hospital, IRCCS, viale di San Paolo 15, 00146, Rome, Italy.

Donatella Del Bufalo (D)

Preclinical Models and New Therapeutic Agents Unit, IRCCS-Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.

Mohammad Salik Zeya Ansari (MS)

Department of Biology and Biotechnology "Charles Darwin", Sapienza University of Rome, P. le A. Moro 5, 00185, Rome, Italy; Institute of Molecular Biology and Pathology, National Research Council (CNR), Via degli Apuli 4, 00185, Rome, Italy.

Nevena Tomašević (N)

Kragujevac Center for Computational Biochemistry, Department of Chemistry, Faculty of Science, University of Kragujevac, Radoja Domanovića 12, 34000, Kragujevac, P.O. Box 60, Serbia.

Milan Mladenović (M)

Kragujevac Center for Computational Biochemistry, Department of Chemistry, Faculty of Science, University of Kragujevac, Radoja Domanovića 12, 34000, Kragujevac, P.O. Box 60, Serbia.

Monica Viviano (M)

Department of Pharmacy, University of Salerno, via Giovanni Paolo II, 132, 84084, Fisciano, SA, Italy.

Gianluca Sbardella (G)

Department of Pharmacy, University of Salerno, via Giovanni Paolo II, 132, 84084, Fisciano, SA, Italy.

Rossella Rota (R)

Department of Oncohematology, Bambino Gesù Children's Hospital, IRCCS, viale di San Paolo 15, 00146, Rome, Italy.

Daniela Trisciuoglio (D)

Preclinical Models and New Therapeutic Agents Unit, IRCCS-Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy; Institute of Molecular Biology and Pathology, National Research Council (CNR), Via degli Apuli 4, 00185, Rome, Italy.

Saverio Minucci (S)

Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, via Adamello 16, 20139, Milan, Italy; Department of Biosciences, University of Milan, Via Festa del Perdono 7, 20122, Milano, Italy.

Andrea Mattevi (A)

Department of Biology and Biotechnology, University of Pavia, Via Ferrata 9, 27100, Pavia, Italy.

Dante Rotili (D)

Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185, Rome, Italy. Electronic address: dante.rotili@uniroma1.it.

Antonello Mai (A)

Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185, Rome, Italy; Pasteur Institute, Cenci-Bolognetti Foundation, Sapienza University of Rome, P. le A. Moro 5, 00185, Rome, Italy. Electronic address: antonello.mai@uniroma1.it.

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Classifications MeSH

questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Novel non-covalent LSD1 inhibitors endowed...
questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Croissance › Processus de croissance cellulaire › Prolifération cellulaire › Novel non-covalent LSD1 inhibitors endowed...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Novel non-covalent LSD1 inhibitors endowed...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Oxidoreductases › Oxidoreductases acting on CH-NH group donors › Oxidoreductases, (N-demethylating) › Histone Demethylases › Novel non-covalent LSD1 inhibitors endowed...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Novel non-covalent LSD1 inhibitors endowed...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Leucémies › Novel non-covalent LSD1 inhibitors endowed...