LSD1: Biologic Roles and Therapeutic Targeting

Figures & data

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.

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).

Table 1.  Pharmacologic inhibitors of lysine-specific demethylase 1 with proven cellular or functional effects.

Drug name	Drug type	Disease setting with potential efficacy	Cellular or functional effect	Ref.
ORY1001^†	Tranylcypromine derivative	Acute leukemia	In Phase I clinical trials in acute leukemia; a related compound OG86 promotes differentiation in vitro and retards MLL-AF9 leukemogenesis in vivo	[53,90]
GSK2879552^†	Tranylcypromine derivative	AML; SCLC	In Phase I clinical trials in AML and SCLC; Predominantly cytostatic effect in multiple cell lines in vitro and in vivo	[91]
RN-1^†	Tranylcypromine derivative	AML; sickle cell disease	AML cell differentiation, apoptosis and growth impairment in vitro and in vivo; induction of fetal hemoglobin synthesis with reduction of sickle cell disease in mice	[92,102]
ORY2001^†	Tranylcypromine derivative	Alzheimer’s disease	Dual LSD1/MAO inhibitor. Rescue of memory and learning defects in a mouse model	[53]
SP2509^‡	Benzohydrazide	Ewing sarcoma, AML	Differentiation, apoptosis and growth impairment in vitro and in vivo; synergy with panobinostat in vivo	[93,103]
Namoline^‡	Nonpeptidic proparglylamine	Prostate cancer	Proliferation arrest	[94]
CBB1007/CBB1003^‡	Nonpeptide chemical scaffold	SOX2^+ squamous cell carcinoma	Differentiation and cell cycle arrest	[95,96]
2d^‡	Polyamine analogue	AML	Cell growth inhibition, global changes on chromatin modifications and transcription with re-expression of aberrantly silenced genes	[100]

^†Indicates inhibitors with an irreversible mechanism of action.

^‡Indicates inhibitors with a reversible mechanism of action.

AML: Acute myeloid leukemia; SCLC: Small-cell lung cancer.

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