The lysine-specific demethylase LSD1 is an epigenetic FAD-dependent enzyme that, by removing in a context and substrate-dependent fashion specific methyl marks on the lysine residues of histone and non-histone proteins, plays a significant role in leukemia, and is also overexpressed in many other types of tumor (breast, lung, colon, prostate, bladder, etc.). More in detail, in hormone-(in)dependent cancers LSD1 plays a vital role in promoting cell proliferation and development, and it is also involved in cell migration, invasion and metastasis. To date, despite many LSD1 inhibitors (LSD1i) have been reported due to the relevant role of this enzyme in cancer, only two tranylcypromine(TCP)-based compounds, ORY-1001 and GSK2879552, have entered clinical trials for selected subtypes of acute myeloid leukemia (AML).
The aim of the present project is to develop new irreversible and reversible LSD1i as potential therapeutic tools for cancer. Moreover, since the DNMT and HDAC inhibitors actually approved by FDA for cancer suffer from strong side effects, selectivity and/or metabolic stability issues, and LSD1i despite their high preclinical potential as single agents in cancer have not been approved as drugs yet, we have thought that dual LSD1/DNMT and LSD1/HDAC inhibitors could show a uniquely favorable pharmacological profile with an improved therapeutic window relative to single agents. For these reasons, starting from current knowledge of pharmacophore characteristics of existing uni-functional HDAC or DNMT and LSD1 targeting compounds, we are going to develop and validate in different cancer models hybrid compounds containing the standard structural elements for HDAC or DNMT inhibition, tethered to a FAD-reactive warhead (either TCP or phenelzine) as potential dual-inhibitors in order to explore their anticancer effects respect to single-target inhibitors.