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.

Novel non-covalent LSD1 inhibitors endowed with anticancer effects in leukemia and solid tumor cellular models / Menna, M.; Fiorentino, F.; Marrocco, B.; Lucidi, A.; Tomassi, S.; Cilli, D.; Romanenghi, M.; Cassandri, M.; Pomella, S.; Pezzella, M.; Del Bufalo, D.; Zeya Ansari, M. S.; Tomasevic, N.; Mladenovic, M.; Viviano, M.; Sbardella, G.; Rota, R.; Trisciuoglio, D.; Minucci, S.; Mattevi, A.; Rotili, D.; Mai, A.. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 237:(2022). [10.1016/j.ejmech.2022.114410]

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

Menna M.
Co-primo
;
Fiorentino F.
Co-primo
;
Marrocco B.;Lucidi A.;Cilli D.;Cassandri M.;Zeya Ansari M. S.;Trisciuoglio D.;Rotili D.
Penultimo
;
Mai A.
Ultimo
2022

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.
cancer; drug discovery; histone lysine methyltransferases; lysine-specific demethylase 1; polypharmacology
01 Pubblicazione su rivista::01a Articolo in rivista
Novel non-covalent LSD1 inhibitors endowed with anticancer effects in leukemia and solid tumor cellular models / Menna, M.; Fiorentino, F.; Marrocco, B.; Lucidi, A.; Tomassi, S.; Cilli, D.; Romanenghi, M.; Cassandri, M.; Pomella, S.; Pezzella, M.; Del Bufalo, D.; Zeya Ansari, M. S.; Tomasevic, N.; Mladenovic, M.; Viviano, M.; Sbardella, G.; Rota, R.; Trisciuoglio, D.; Minucci, S.; Mattevi, A.; Rotili, D.; Mai, A.. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 237:(2022). [10.1016/j.ejmech.2022.114410]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1635728
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