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Lysine Methyltransferases and Their Inhibitors

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Chemical Epigenetics

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 33))

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Abstract

Since 2000, the histone methyltransferases that catalyze the methylation of a number of histone and nonhistone substrates have been discovered.

A growing body of literature is indicating that lysine methyltransferases (KMTs) play a crucial role for transcriptional regulation and are involved in cancer and various other human diseases, thus being of high interest as potential therapeutic targets.

In this book chapter, we highlight the discovery, characterization, and application of selective KMT inhibitors, useful for dissecting their physiological functions as well as their disease implications.

Over the past decade, there has been an impressive progress regarding the KMT inhibitor discovery, especially conjugating the research interest with the available and novel techniques including new assay methods, high-throughput screening, structural biology, and medicinal chemistry approaches. Our goal is to point out herein key advances, challenges, possible future opportunities, and directions, regarding KMT modulation in a preclinical and clinical setting.

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Abbreviations

5-HT2A:

5-Hydroxytryptamine receptor 2A

AML:

Acute myeloid leukemia

ASH2L:

ASH2 like histone lysine methyltransferase complex subunit

CARM1:

Coactivator-associated arginine methyltransferase 1

DLBCL:

Diffuse large B-cell lymphoma

DNMT:

DNA methyltransferase

DNMTi:

DNA methyltransferase inhibitor

DOT1L:

Disruptor of telomeric silencing 1-like

EED:

Embryonic ectoderm development

EHMT1:

Euchromatin histone methyltransferase 1 (see also GLP)

EHMT2:

Euchromatin histone methyltransferase 2 (see also G9a)

ERα:

Estrogen receptor alpha

EZH1:

Enhancer of zeste homologue 1

EZH2:

Enhancer of zeste homologue 2

FP:

Fluorescence polarization

G9a:

Euchromatic histone-lysine N-methyltransferase 2 (EHMT2)

GLP:

G9a-like protein (EHMT1)

GPCRs:

G protein-coupled receptor

H1:

Histamine receptor 1

H3K9:

Lysine 9 of histone 3

H3K9me2:

Demethylated lysine 9 of histone 3

HbF:

Hemoglobin F

HCT116:

Colon colorectal carcinoma cell line

HDACi:

Histone deacetylase inhibitors

HEK293T:

Human embryonic kidney cell line

HL60:

Human leukemia cell line

HSP90:

Heat shock protein 90

HTS:

High-throughput screening

IUGR:

Intrauterine growth restriction

KARPAS-422:

Lymphoma cell line

KMTs:

Lysine methyltransferases

LnCaP:

Prostate adenocarcinoma cells

MAP 3K2:

Mitogen-activated protein kinase kinase kinase 2

MCF10A:

Non-tumorigenic epithelial cell line

MCF7:

Breast cancer cell line

MDA-MB-231:

Human breast cancer cell line

MLL:

Mixed-lineage leukemia

MOA:

Mechanism of action

MV4–11 (MLL-AF4), MOLM-13 (MLL-AF9), and THP1 (MLL-AF9):

MLL-rearranged cell lines

MYND:

Myeloid translocation protein-8, Nervy, and DEAF-1

PARP1:

Poly(ADP-ribose)-polymerase 1

PC-3:

Prostate cancer cell line

PCNA:

Proliferating cell nuclear antigen

PK:

Physical-chemical (properties)

PKMTs:

Protein lysine methyltransferases

PML-NB:

Promyelocytic leukemia protein nuclear bodies

PMTs:

Protein methyltransferases

PPAR-γ:

Peroxisome proliferator-activated receptor gamma

PPI:

Protein-protein interaction

PRC2:

Polycomb-repressive complex 2

PRMTs:

Protein arginine methyltransferases

PWS:

Prader-Willi syndrome

Rb:

Retinoblastoma

RBBP5:

Retinoblastoma-binding protein 5

RE-IIBP:

Response element II-binding protein

RNMTs:

RNA methyltransferases

SAH:

S-adenosyl homocysteine

SAM:

S-adenosyl-l-methionine

SAR:

Structure-activity relationship

SCD:

Sickle cell disease

SCLC:

Small cell lung cancer

SET:

Nuclear proto-oncogene

SETD2:

SET domain containing 2 histone methyltransferase

SETD7:

SET domain containing 7 histone methyltransferase

SETD8:

SET domain containing 8 histone methyltransferase

SETDB1:

SET domain bifurcated 1

SMYD:

SET and MYND domain-containing

SUM159:

Breast cancer cell line

SUV:

Histone-lysine N-methyltransferase

SUZ12:

Subunit polycomb-repressive complex 2

U2OS:

Osteosarcoma cell line

U937:

Histiocytic lymphoma cell line

VEGFR1:

Vascular endothelial growth factor receptor 1

WDR5:

WD repeat-containing protein 5

WT:

Wild type

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  1. Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, Italy

    Giulia Stazi, Clemens Zwergel & Sergio Valente

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  2. Clemens Zwergel
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    Antonello Mai

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Stazi, G., Zwergel, C., Valente, S. (2019). Lysine Methyltransferases and Their Inhibitors. In: Mai, A. (eds) Chemical Epigenetics. Topics in Medicinal Chemistry, vol 33. Springer, Cham. https://doi.org/10.1007/7355_2019_72

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