Drug Design Concepts for LSD1‐Selective Inhibitors

Abstract

Lysine‐specific demethylase 1 (LSD1) is one of the flavin‐dependent oxidases and is involved in many cellular processes by controlling the methylation of histone H3. Recently, it has been reported that LSD1 is associated with several diseases such as cancer, metabolic disorders, and psychiatric diseases. Thus, LSD1 is an attractive molecular target for the treatment of these diseases, and its inhibitors are predicted as therapeutic agents. Although a variety of LSD1 inhibitors have been reported to date, many of them show insufficient activities and selectivity toward LSD1. Meanwhile, we identified several LSD1‐selective inhibitors using target‐guided synthesis strategies based on our original ideas. Our LSD1 inhibitors show not only potent LSD1‐selective inhibitory activities, but also unique bioactivities both in vitro and in vivo. This account highlights our drug design concepts for and identification of LSD1‐selective inhibitors.

Reversible Lysine Specific Demethylase 1 (LSD1) Inhibitors: A Promising Wrench to Impair LSD1

“…Significant advances have been made toward the discovery of effective LSD1 inhibitors over the past decade. ,− Particularly, six tranylcypromine (TCP)-based irreversible LSD1 inhibitors are currently undergoing clinical trials alone or in combination with other drugs for the treatment of SCLC and AML, including TCP, GSK2879552, IMG-7289, ORY-1001, INCB059872, and ORY-2001 (Figure A). − Very recently, we have provided an extensive review of the development of TCP-based irreversible LSD1 inhibitors …”

Pharmacological Inhibition of LSD1 for Cancer Treatment

“…LSD1 is involved in regulating many typical biological processes, including the epithelial-mesenchymal transition (EMT), stemness, cell motility, and through its ability to repress or activate transcription by demethylating H3K4me2/1 or H3K9me2/1, respectively (Figure 2C) [26]. LSD1 also demethylates some non-histone proteins and mediates the progression of some cancers [2,6,7,8,9].…”

“…Some researchers have developed LSD1 inhibitors via mimicking the lysine group at the meta-position (NCL-1) or the para-position (NCL-2) of the phenyl ring, and the resulting compounds have exhibited improved inhibitory activities for LSD1 and selectivity for LSD1 over MAOs [114]. Mechanistically, NCL-1 and NCL-2 irreversibly inactivated LSD1 through forming a covalent bond with FAD, which induced the accumulation of H3K4me2, leading to the transcriptional upregulation of tumor suppressor genes and eventually repression of cancer cell growth [26]. Subsequently, NCL-1 derivatives were developed with the aim of improving their biological activity [112], and these analogues exhibited good anti-cancer activities in solid tumors, such as breast cancer [119], prostate cancer [120], and glioma [121,122] in cellulo and/or in vivo.…”

Epigenetic treatment combinations to effectively target cisplatin‐resistant germ cell tumors: past, present, and future considerations

“…Lysine-specific histone demethylase 1 (LSD1/KDM1A) is one of the flavin-dependent monoamine oxidoreductase which removes methyl groups from histones H3K4me1/2 and H3K9me1/2 (Yang et al, 2018). LSD1 is aberrantly overexpressed in many cancers, such as neuroblastoma, bladder, breast, colorectal, gastric, lung, and neuroendocrine cancers (Bennani-Baiti et al, 2012) and is therefore an attractive molecular target for anti-neoplastic treatment options (Ota & Suzuki, 2018;Yang et al, 2018). An example of an epigenetic dual inhibitor was recently described by Kalin et al (Kalin et al, 2018).…”