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Review
. 2016 Aug;8(8):1103-16.
doi: 10.2217/epi-2016-0009. Epub 2016 Aug 1.

LSD1: biologic roles and therapeutic targeting

Alba Maiques-Diaz  1 , Tim Cp Somervaille  1
Affiliations
Review

LSD1: biologic roles and therapeutic targeting

Alba Maiques-Diaz et al. Epigenomics. 2016 Aug.

Abstract

LSD1 (KDM1A; BHC110; AOF2) was the first protein reported to exhibit histone demethylase activity and has since been shown to have multiple essential roles in mammalian biology. Given its enzymatic activity and its high-level expression in many human malignancies, a significant recent focus has been the development of pharmacologic inhibitors. Here we summarize structural and biochemical knowledge of this important epigenetic regulator, with a particular emphasis on the functional and preclinical studies in oncology that have provided justification for the evaluation of tranylcypromine derivative LSD1 inhibitors in early phase clinical trials.

Keywords: GSK2879552; LSD1; ORY1001; acute myeloid leukemia; histone demethylase; small-cell lung cancer.

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Conflict of interest statement

Financial & competing interests disclosure A Maiques-Diaz and T Somervaille are supported by Cancer Research UK Grant Number C5759/A12328. T Somervaille has ongoing research collaborations with Oryzon Genomics and consults for Imago Biosciences. 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. No writing assistance was utilized in the production of this manuscript.

Figures

<b>Figure 1.</b>
Figure 1.. LSD1 protein complex, structure and enzymatic activity.
(A) Schematic illustrates the core components of the CoREST transcription repressor complex recruited to chromatin in association with TF. (B) Biochemical steps in the FAD-dependent demethylation of monomethyl lysine by LSD1 (C) x-ray structure representation of LSD1:RCOR1 bound to a peptide substrate. Domains are highlighted in colors. (D) Details of the catalytic site from the LSD1:CoREST structure highlighting the flavin moiety of FAD (gray carbon atoms), the amine oxidase domain (cyan) and the histone H3 peptide (pink). The position of LSD1 lysine 661 is indicated, as is that of lysine 4 of the histone peptide, here shown as MET-4. For purposes of the crystallization, lysine was replaced by methionine in view of the higher binding affinity of the pLys4Met peptide. Images were generated using PyMOL (Molecular Graphics System, Schrödinger, LLC) and a published structure [12]. FAD: Flavin-adenine dinucleotide; TF: Transcription factor.
<b>Figure 2.</b>
Figure 2.. Pharmacologic inhibitors of LSD1.
Chemical structures of (A) tranylcypromine; (B) GSK2879552; (C) OG86 (also known as Compound B) and (D) ORY1001. Images were generated using ChemDraw (PerkinElmer Inc).
See this image and copyright information in PMC

References

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