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Medicinal Chemistry Research

, Volume 28, Issue 4, pp 395–416 | Cite as

Quinazolines as inhibitors of chromatin-associated proteins in histones

  • Frida S. Herrera-Vázquez
  • Francisco Hernández-Luis
  • José L. Medina FrancoEmail author
Review Article
  • 182 Downloads

Abstract

It is increasing the evidence that quinazolines are inhibitors of chromatin-associated proteins in histones. Quinazolines have a broad structural diversity among the structural classes that have been designed. Herein, we review the development of selective and potent quinazolines highlighting the current state of these molecules with an emphasis on the structural requirements for the interaction within the target. Chemical synthesis and results of the biological assays in vitro or in vivo of these compounds are also discussed. There is extensive evidence that support quinazoline derivatives as inhibitors of histone methyltransferase (G9a) and G9a-like protein (GLP). There is one quinazoline analogue that inhibits an extra-terminal bromodomain motif (BET) and that is on clinical trials as potential treatment for different chronic diseases. There is also clinical evidence that quinazolines act as dual inhibitors targeting histone deacetylases (HDACs) Zn2+-dependent and kinase receptors for the potential treatment of cancer. Additional proposals of quinazoline structures are being evaluated as inhibitors targeting two or more chromatin-associated proteins simultaneously. Therefore, further improvements in synthetic methods, computational studies, and additional biological assays in vitro and in vivo remain to be addressed.

Keywords

Quinazoline chromatin-associated proteins Epigenetic Histone modifiers Inhibitors 

Abbreviations

AML

acute myeloid leukemia

ApoA1

apolipoprotein A1

BRDs

bromodomains

CRDs

chromodomains

CLint

intrinsic clearance

DNA

deoxyribonucleic acid

EC50

half maximal effective concentration

FAD+

flavin adenine dinucleotide

G9a

euchromatic histone-lysine N-methyltransferase 2

GLP

G9a-like protein

HDACs

histone deacetylases

HER1

epidermal growth factor receptor

HER2

human epidermal growth factor receptor-type2

H3K9Me2

dimethylated lysine 9 histone 3

HKMT

histone lysine methyltransferases

IC50

half maximal inhibitory concentration

iPS

reprogramming induced pluripotent stem cells

Kac

acetylated lysine

LSD1

lysine-specific demethylase 1

MAO

monoamine oxidases

MBT

malignant brain tumor

Myc

proto-oncogenes that code for transcription factors

NAD+

nicotinamide adenine dinucleotide

PTMs

post-translational modification,

PPARγ

peroxisome proliferator-activated receptor gamma

PHKMT

Plasmodium histone lysine methyltransferase

VEGFR-2

vascular endothelial growth factor receptor

Notes

Acknowledgements

FSH-V acknowledges the MSc scholarship from CONACyT no. 629489. Authors are grateful to Rodrigo Aguayo-Ortiz and Jose A. Chamorro-Espino for their major contributions to prepare the figures of the manuscript. JLM-F thanks Consejo Nacional de Ciencia y Tecnologia (CONACyT) for grant 282785.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

44_2019_2300_MOESM1_ESM.pdf (57 kb)
Supplementary Information

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Facultad de Química, Departamento de FarmaciaUniversidad Nacional Autónoma de MéxicoMexicoMexico

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