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Structure-activity relationship studies of G9a-like protein (GLP) inhibitors

Journal Article · · Bioorganic and Medicinal Chemistry
 [1];  [2];  [1];  [2];  [2];  [2];  [1];  [2];  [2];  [1];  [2];  [1]
  1. Icahn School of Medicine at Mount Sinai, New York, NY (United States)
  2. Univ. of Toronto, ON (Canada)
+ Show Author Affiliations
Given the high homology between the protein lysine methyltransferases G9a-like protein (GLP) and G9a, it has been challenging to develop potent and selective inhibitors for either enzyme. Recently, we reported two quinazoline compounds, MS0124 and MS012, as GLP selective inhibitors. To further investigate the structure–activity relationships (SAR) of the quinazoline scaffold, we designed and synthesized a range of analogs bearing different 2-amino substitutions and evaluated their inhibition potencies against both GLP and G9a. These studies led to the identification of two new GLP selective inhibitors, 13 (MS3748) and 17 (MS3745), with 59- and 65-fold higher potency for GLP over G9a, which were confirmed by isothermal titration calorimetry (ITC). Crystal structures of GLP and G9a in complex with 13 and 17 provide insight into the interactions of the inhibitors with both proteins. Additionally, we generated GLP selective inhibitors bearing a quinoline core instead of the quinazoline core.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
Canada Foundation for Innovation (CFI); AbbVie; Bayer Pharma AG; Boehringer Ingelheim; Eshelman Institute for Innovation; Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP); Genome Canada; Innovative Medicines Initiative; Janssen, Merck & Co.; National Institutes of Health (NIH); Novartis Pharma AG; Ontario Ministry of Economic Development and Innovation; Pfizer; Takeda; Wellcome Trust
OSTI ID:
1390876
Journal Information:
Bioorganic and Medicinal Chemistry, Journal Name: Bioorganic and Medicinal Chemistry Journal Issue: 16 Vol. 25; ISSN 0968-0896
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

References (48)

A Chemical Tool for In Vitro and In Vivo Precipitation of Lysine Methyltransferase G9a journal January 2014
Discovery, design and synthesis of 6 H -anthra[1,9- cd ]isoxazol-6-one scaffold as G9a inhibitor through a combination of shape-based virtual screening and structure-based molecular modification journal November 2016
Discovery of novel small molecule inhibitors of lysine methyltransferase G9a and their mechanism in leukemia cell lines journal October 2016
Adding a Lysine Mimic in the Design of Potent Inhibitors of Histone Lysine Methyltransferases journal July 2010
Unexpected Distinct Roles of the Related Histone H3 Lysine 9 Methyltransferases G9a and G9a-Like Protein in Myoblasts journal June 2016
Reversal of H3K9me2 by a Small-Molecule Inhibitor for the G9a Histone Methyltransferase journal February 2007
Methylation of a Histone Mimic within the Histone Methyltransferase G9a Regulates Protein Complex Assembly journal August 2007
Negative Regulation of Hypoxic Responses via Induced Reptin Methylation journal July 2010
Histone H3 Lysine 56 Methylation Regulates DNA Replication through Its Interaction with PCNA journal April 2012
A General Molecular Affinity Strategy for Global Detection and Proteomic Analysis of Lysine Methylation journal May 2013
Control of Cognition and Adaptive Behavior by the GLP/G9a Epigenetic Suppressor Complex journal December 2009
The role of chromatin repressive marks in cognition and disease: A focus on the repressive complex GLP/G9a journal October 2015
Discovery of Potent and Selective Inhibitors for G9a-Like Protein (GLP) Lysine Methyltransferase journal February 2017
A Small-Molecule Probe of the Histone Methyltransferase G9a Induces Cellular Senescence in Pancreatic Adenocarcinoma journal April 2012
Chemical Probes of Histone Lysine Methyltransferases journal November 2014
Protein Lysine Methyltransferase G9a Inhibitors: Design, Synthesis, and Structure Activity Relationships of 2,4-Diamino-7-aminoalkoxy-quinazolines. journal August 2010
Optimization of Cellular Activity of G9a Inhibitors 7-Aminoalkoxy-quinazolines journal September 2011
Discovery of an in Vivo Chemical Probe of the Lysine Methyltransferases G9a and GLP journal October 2013
Selective Inhibitors of Protein Methyltransferases journal December 2014
Discovery of a 2,4-Diamino-7-aminoalkoxyquinazoline as a Potent and Selective Inhibitor of Histone Lysine Methyltransferase G9a journal December 2009
Analogues of the Natural Product Sinefungin as Inhibitors of EHMT1 and EHMT2 journal February 2014
Discovery and Development of Potent and Selective Inhibitors of Histone Methyltransferase G9a journal January 2014
Histone methyltransferase G9a contributes to H3K27 methylation in vivo journal November 2010
EHMT1 controls brown adipose cell fate and thermogenesis through the PRDM16 complex journal November 2013
Protein lysine methyltransferase G9a acts on non-histone targets journal April 2008
Targeting the histone methyltransferase G9a activates imprinted genes and improves survival of a mouse model of Prader–Willi syndrome journal December 2016
The ankyrin repeats of G9a and GLP histone methyltransferases are mono- and dimethyllysine binding modules journal February 2008
Structural basis for G9a-like protein lysine methyltransferase inhibition by BIX-01294 journal February 2009
Identification of 2,4-diamino-6,7-dimethoxyquinoline derivatives as G9a inhibitors journal January 2014
Lysine methyltransferase G9a methylates the transcription factor MyoD and regulates skeletal muscle differentiation journal January 2012
SET Domain-containing Protein, G9a, Is a Novel Lysine-preferring Mammalian Histone Methyltransferase with Hyperactivity and Specific Selectivity to Lysines 9 and 27 of Histone H3 journal April 2001
A Role for Widely Interspaced Zinc Finger (WIZ) in Retention of the G9a Methyltransferase on Chromatin journal October 2015
Substrate Specificity and Kinetic Mechanism of Mammalian G9a Histone H3 Methyltransferase journal December 2004
Dynamic Histone H1 Isotype 4 Methylation and Demethylation by Histone Lysine Methyltransferase G9a/KMT1C and the Jumonji Domain-containing JMJD2/KDM4 Proteins journal March 2009
Functional Crosstalk Between Lysine Methyltransferases on Histone Substrates: The Case of G9A/GLP and Polycomb Repressive Complex 2 journal June 2015
Histone methyltransferases G9a and GLP form heteromeric complexes and are both crucial for methylation of euchromatin at H3-K9 journal April 2005
The methyltransferase G9a regulates HoxA9-dependent transcription in AML journal February 2014
Recognition of H3K9 methylation by GLP is required for efficient establishment of H3K9 methylation, rapid target gene repression, and mouse viability journal January 2015
G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis journal July 2002
Phaser crystallographic software journal July 2007
Coot model-building tools for molecular graphics journal November 2004
PHENIX: a comprehensive Python-based system for macromolecular structure solution journal January 2010
Towards automated crystallographic structure refinement with phenix.refine journal March 2012
Refinement of Macromolecular Structures by the Maximum-Likelihood Method journal May 1997
Disruption of the gene Euchromatin Histone Methyl Transferase1 (Eu-HMTase1) is associated with the 9q34 subtelomeric deletion syndrome journal April 2005
Regulation of cell differentiation and function by the euchromatin histone methyltranserfases G9a and GLP journal February 2016
Deregulation of histone lysine methyltransferases contributes to oncogenic transformation of human bronchoepithelial cells journal January 2008
Histone H1 variant-specific lysine methylation by G9a/KMT1C and Glp1/KMT1D journal January 2010

Cited By (5)

Quercetin modifies 5′CpG promoter methylation and reactivates various tumor suppressor genes by modulating epigenetic marks in human cervical cancer cells journal June 2019
Quinazolines as inhibitors of chromatin-associated proteins in histones journal February 2019
Delineating the active site architecture of G9a lysine methyltransferase through substrate and inhibitor binding mode analysis: a molecular dynamics study journal November 2018
Delineating the active site architecture of G9a lysine methyltransferase through substrate and inhibitor binding mode analysis: a molecular dynamics study text January 2018
Delineating the active site architecture of G9a lysine methyltransferase through substrate and inhibitor binding mode analysis: a molecular dynamics study text January 2018

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Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
59 BASIC BIOLOGICAL SCIENCES
G9a
GLP
Inhibitor
Quinazoline
Quinoline