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pp 1-35 | Cite as

Lysine Methyltransferases and Their Inhibitors

  • Giulia Stazi
  • Clemens Zwergel
  • Sergio ValenteEmail author
Chapter
Part of the Topics in Medicinal Chemistry book series

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.

Keywords

Cancer Chromatin DOT1L Epigenetic modulators EZH2 G9a Lysine methyltransferases SETs SUVs 

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

Notes

Compliance with Ethical Standards

Conflict of Interest: The authors declare no conflict of interest.

Ethical Approval: This article does not contain any studies with human participants or animals performed by any of the authors.

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© Springer Nature Switzerland AG  2019

Authors and Affiliations

  1. 1.Department of Drug Chemistry and TechnologiesSapienza University of RomeRomeItaly

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