LSD1 inhibitors: a patent review (2010-2015)

ABSTRACT

Introduction: Lysine demethylase 1 (LSD1) plays an important role in mediating the expression of genes involved in cancer and non-cancer diseases such as viral infections, cardiovascular and neurodegenerative disorders. It is involved in a number of processes from adipogenesis to cell adhesion to viral latency, regulating several cell pathways related with proliferation, development, and cell cycle control. Numerous chemical entities have been studied in recent years and some of them entered the clinical arena.

Areas covered: This review summarizes recent efforts in the drug development of LSD1 inhibitors reported in the patent literature covering the 2010-2015 period, including their potential use as therapeutics in cancerous, neurological, inflammatory, cardiovascular, and viral diseases.

Expert opinion: The development of novel potent and selective LSD1 inhibitors is ongoing, in order to improve their potency and selectivity against specific types of cancer or non-cancer diseases. More in-depth studies are required to assess the role of LSD1 inhibitors in the expression of LSD1 target genes, for a better assessment of the biochemistry underlying their efficacy, and to provide evidence for any possible side effects. Furthermore, an interesting therapeutic approach is the use of LSD1 inhibitors in conjunction with other epidrugs to combine their therapeutic potential, leading to innovative, personalized treatments.

KEYWORDS:

• Cancer
• epigenetics
• lysine specific demethylase 1
• viral infections
• small molecule inhibitors

Article highlights

• Recent patents 2010–2015 on drug design strategies for developing inhibitors of LSD1, a key epigenetic target, that could represent a promising future therapy for cancer and noncancerous diseases such as neurodegeneration, inflammation, and viral infections are presented.

• A large number of patents describe TCP-containing compounds with substitutions on both the aromatic ring and on the amine function. These compounds irreversibly inhibit LSD1, and some of them selectively block LSD1 over MAOs and display good antiproliferative activity in cancer cells.


• Efforts have been done to obtain LSD1 reversible inhibitors. Phenelzine-analogs and hydrazide/hydrazine-containing derivatives comprise inhibitors with inhibiting potency in the nanomolar range and a good selectivity for LSD1. Tested in different cancer cells, they displayed a dose-dependent reduction of cell viability and induced an increase in H3K4 methylation levels.

• Both irreversible and reversible LSD1 inhibitors have been shown to increase H3K4me2 levels in a dose-dependent manner in treated cells and induce re-expression of LSD1-related genes such as SCN3a, CHRM4, FOXA2, HMOX, GAD1, CD14, and Gfi-1b.

• The involvement of LSD1 in many cell pathways and its implication in disorders different from cancer is becoming more and more evident. Hence, many groups studied LSD1 inhibitors for their potential application different from cancer therapy, such as viral infections and latency, inflammation and cardiovascular diseases, neurodegeneration, adipogenesis, and lipid metabolism.

• A TCP-containing derivative is currently undergoing phase I clinical trial for the treatment of relapsed/refractory small cell lung carcinoma and AML.

This box summarizes the key points contained in the article.

Declaration of interest

This work was supported by IIT-Sapienza Project, the RF-2010-2318330 grant from the Italian Ministry of Health, the Sapienza Ateneo Project 2013, the IIT-Sapienza Project, the FP7 Projects BLUEPRINT/282510 and A-PARADDISE/602080. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.