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, Martina; Fiorentino, Francesco; Marrocco, Biagina; Lucidi, Alessia; Tomassi, Stefano; Cilli, Domenica; Romanenghi, Mauro; Cassandri, Matteo; Pomella, Silvia; Pezzella, Michele; Del Bufalo, Donatella; Zeya Ansari, Mohammad Salik; Tomašević, Nevena; Mladenović, Milan; Viviano, Monica; Sbardella, Gianluca; Rota, Rossella; Trisciuoglio, Daniela; Minucci, Saverio; Mattevi, Andrea; Rotili, Dante; Mai, Antonello. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 1768-3254. - 237:(2022), pp. 114410-114432. [10.1016/j.ejmech.2022.114410]
Novel non-covalent LSD1 inhibitors endowed with anticancer effects in leukemia and solid tumor cellular models
Tomassi, Stefano;
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
