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

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 50 range, highlighting a crucial anticancer role for LSD1 inhibition and suggesting no added value for the simultaneous G9a inhibition in these tumor cell lines. [Display omitted] • Novel potent and selective non-covalent LSD1 inhibitors are presented. • The crystal structure of LSD1 inhibitor 7 in complex with LSD1-CoREST unveils an unusual binding mode. • The most potent LSD1 inhibitors (7 , 8 and 29) display sub-micromolar antiproliferative effects in leukemia cells. • The same compounds inhibit breast cancer and rhabdomyosarcoma cell proliferation. • Functional assays confirm the inhibition of LSD1 at cellular level in both solid and hematological cancer cell lines. [ABSTRACT FROM AUTHOR]