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

Martina Menna; Francesco Fiorentino; Biagina Marrocco; Alessia Lucidi; Stefano Tomassi; Domenica Cilli; Mauro Romanenghi; Matteo Cassandri; Silvia Pomella; Michele Pezzella; Donatella Del Bufalo; Mohammad Salik Zeya Ansari; Nevena Tomašević; Milan Mladenović; Monica Viviano; Gianluca Sbardella; Rossella Rota; Daniela Trisciuoglio; Saverio Minucci; Andrea Mattevi; Dante Rotili; Antonello Mai

doi:10.1016/j.ejmech.2022.114410

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

Eur J Med Chem. 2022 Jul 5:237:114410. doi: 10.1016/j.ejmech.2022.114410. Epub 2022 Apr 27.

Authors

Martina Menna¹, Francesco Fiorentino¹, Biagina Marrocco², Alessia Lucidi¹, Stefano Tomassi³, Domenica Cilli⁴, Mauro Romanenghi⁴, Matteo Cassandri⁵, Silvia Pomella⁵, Michele Pezzella⁵, Donatella Del Bufalo⁶, Mohammad Salik Zeya Ansari⁷, Nevena Tomašević⁸, Milan Mladenović⁸, Monica Viviano⁹, Gianluca Sbardella⁹, Rossella Rota⁵, Daniela Trisciuoglio¹⁰, Saverio Minucci¹¹, Andrea Mattevi², Dante Rotili¹², Antonello Mai¹³

Affiliations

¹ Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185, Rome, Italy.
² Department of Biology and Biotechnology, University of Pavia, Via Ferrata 9, 27100, Pavia, Italy.
³ Department of Pharmacy, University of Naples "Federico II", via Domenico Montesano 49, 80131, Naples, Italy.
⁴ Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, via Adamello 16, 20139, Milan, Italy.
⁵ Department of Oncohematology, Bambino Gesù Children's Hospital, IRCCS, viale di San Paolo 15, 00146, Rome, Italy.
⁶ Preclinical Models and New Therapeutic Agents Unit, IRCCS-Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.
⁷ 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.
⁸ Kragujevac Center for Computational Biochemistry, Department of Chemistry, Faculty of Science, University of Kragujevac, Radoja Domanovića 12, 34000, Kragujevac, P.O. Box 60, Serbia.
⁹ Department of Pharmacy, University of Salerno, via Giovanni Paolo II, 132, 84084, Fisciano, SA, Italy.
¹⁰ 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.
¹¹ 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.
¹² Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185, Rome, Italy. Electronic address: dante.rotili@uniroma1.it.
¹³ 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.

PMID: 35525212
DOI: 10.1016/j.ejmech.2022.114410

Abstract

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 IC₅₀ range, highlighting a crucial anticancer role for LSD1 inhibition and suggesting no added value for the simultaneous G9a inhibition in these tumor cell lines.

Keywords: Cancer; Drug discovery; Histone lysine methyltransferases; Lysine-specific demethylase 1; Polypharmacology.

MeSH terms

Cell Line, Tumor
Cell Proliferation
Enzyme Inhibitors* / chemistry
Histone Demethylases
Humans
Leukemia* / drug therapy
Leukemia* / metabolism

Substances

Enzyme Inhibitors
Histone Demethylases