Detailed Exploration around 4-Aminoquinolines Chemical Space to Navigate the Lysine Methyltransferase G9a and DNA Methyltransferase Biological Spaces

Rabal, Obdulia; Sánchez‐Arias, Juan A.; José‐Eneriz, Edurne San; Agirre, Xabier; Miguel, Irene de; Gárate, Leire; Miranda, Estíbaliz; Sáez, Elena; Roa, Sergio; Martínez-Climent, José A.; Liu, Yingying; Wu, Wei; Xu, Min; Prósper, Felipe; Oyarzábal, Julen

doi:10.1021/acs.jmedchem.7b01925

Cited by 26 publications

(71 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The synthesis and biological activity of the three proprietary compounds CM-272, CM-679 and CM-986 has been reported [ 36 – 39 ]. Chemical structures and IC 50 values against EHMT2 (G9a) and DNMT1 are given in Fig.…”

Section: Methodsmentioning

confidence: 99%

Novel pharmacological maps of protein lysine methyltransferases: key for target deorphanization

2018

Self Cite

View full text Add to dashboard Cite

Epigenetic therapies are being investigated for the treatment of cancer, cognitive disorders, metabolic alterations and autoinmune diseases. Among the different epigenetic target families, protein lysine methyltransferases (PKMTs), are especially interesting because it is believed that their inhibition may be highly specific at the functional level. Despite its relevance, there are currently known inhibitors against only 10 out of the 50 SET-domain containing members of the PKMT family. Accordingly, the identification of chemical probes for the validation of the therapeutic impact of epigenetic modulation is key. Moreover, little is known about the mechanisms that dictate their substrate specificity and ligand selectivity. Consequently, it is desirable to explore novel methods to characterize the pharmacological similarity of PKMTs, going beyond classical phylogenetic relationships. Such characterization would enable the prediction of ligand off-target effects caused by lack of ligand selectivity and the repurposing of known compounds against alternative targets. This is particularly relevant in the case of orphan targets with unreported inhibitors. Here, we first perform a systematic study of binding modes of cofactor and substrate bound ligands with all available SET domain-containing PKMTs. Protein ligand interaction fingerprints were applied to identify conserved hot spots and contact-specific residues across subfamilies at each binding site; a relevant analysis for guiding the design of novel, selective compounds. Then, a recently described methodology (GPCR-CoINPocket) that incorporates ligand contact information into classical alignment-based comparisons was applied to the entire family of 50 SET-containing proteins to devise pharmacological similarities between them. The main advantage of this approach is that it is not restricted to proteins for which crystallographic data with bound ligands is available. The resulting family organization from the separate analysis of both sites (cofactor and substrate) was retrospectively and prospectively validated. Of note, three hits (inhibition > 50% at 10 µM) were identified for the orphan NSD1.Electronic supplementary materialThe online version of this article (10.1186/s13321-018-0288-5) contains supplementary material, which is available to authorized users.

show abstract

Section: Methodsmentioning

confidence: 99%

Novel pharmacological maps of protein lysine methyltransferases: key for target deorphanization

2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…Thus, Rabal et al decided to design and synthetize a quinoline analog of UNC0638 98 , compound 100 (Figure ), to be tested against both DNMT1 and G9a through time‐resolved fluorescence resonance energy transfer (TR‐FRET) technique. Competition experiments confirmed that 100 displayed substrate‐competitive inhibition of both targets, with global reduction in H3K9me2 and 5‐methylcytosine (5mC) levels . Unfortunately, 100 did not show any antiproliferative response against ALL CEMO‐1 (GI 50 > 10 µM), DCLBL OCI‐Ly3 and OCI‐Ly10 (0% inhibition at 1 µM) and AML MV4‐11 (GI 50 > 10 µM) cell lines.…”

Section: The Mtdl Approachmentioning

confidence: 96%

“…367 and 5-methylcytosine (5mC) levels. 372,373 Unfortunately, 100 did not show any antiproliferative response against ALL CEMO-1 (GI 50 > 10 µM), DCLBL OCI-Ly3 and OCI-Ly10 (0% inhibition at 1 µM) and AML MV4-11…”

Section: Proteolysis Targeting Chimera Approach Applied To Epigenetmentioning

confidence: 98%

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

Tomaselli

Lucidi

Rotili

et al. 2019

Medicinal Research Reviews

View full text Add to dashboard Cite

Recently, despite the great success achieved by the so‐called “magic bullets” in the treatment of different diseases through a marked and specific interaction with the target of interest, the pharmacological research is moving toward the development of “molecular network active compounds,” embracing the related polypharmacology approach. This strategy was born to overcome the main limitations of the single target therapy leading to a superior therapeutic effect, a decrease of adverse reactions, and a reduction of potential mechanism(s) of drug resistance caused by robustness and redundancy of biological pathways. It has become clear that multifactorial diseases such as cancer, neurological, and inflammatory disorders, may require more complex therapeutic approaches hitting a certain biological system as a whole. Concerning epigenetics, the goal of the multi‐epi‐target approach consists in the development of small molecules able to simultaneously and (often) reversibly bind different specific epi‐targets. To date, two dual histone deacetylase/kinase inhibitors (CUDC‐101 and CUDC‐907) are in an advanced stage of clinical trials. In the last years, the growing interest in polypharmacology encouraged the publication of high‐quality reviews on combination therapy and hybrid molecules. Hence, to update the state‐of‐the‐art of these therapeutic approaches avoiding redundancy, herein we focused only on multiple medication therapies and multitargeting compounds exploiting epigenetic plus nonepigenetic drugs reported in the literature in 2018. In addition, all the multi‐epi‐target inhibitors known in literature so far, hitting two or more epigenetic targets, have been included.

show abstract

“…Based on studies that describe the interactions involved in the molecular recognition of G9a and DNMT1 [1,18,19]. Compound 6 (not present on the PDBs structures reported) was used to guide the development of a protocol that captured the interactions reported for other active compounds.…”

Section: Search For Ideal Conditionsmentioning

confidence: 99%

“…The work published by Rabal, et al (2018) is a key step forward in this analysis. They synthesized a novel series of 4-aminoquinolines as inhibitors of the enzymes lysine methyltransferase (G9a) and DNA methyltransferase 1 (DNMT1).…”

Section: Introductionmentioning

confidence: 99%

Activity Landscape and Molecular Modeling to Explore the SAR of Dual Epigenetic Inhibitors: A Focus on G9a and DNMT1

López-López

Prieto‐Martínez

Medina-Franco

2018

Preprint

View full text Add to dashboard Cite

In this work we discuss the insights from activity landscape, docking and molecular dynamics towards the understanding of the structure-activity relationships of dual inhibitors of major epigenetic targets: lysine metiltransferase (G9a) and DNA metiltranferase 1 (DNMT1). The study was based on a novel data set of 50 published compounds with reported experimental activity for both targets. The activity landscape analysis revealed the presence of activity cliffs, e.g., pairs of compounds with high structure similarity but large activity difference. Activity cliffs were further rationalized at the molecular level by means of molecular docking and dynamics simulations that led to the identification of interactions with key residues involved in the dual activity or selectivity with the epigenetic targets.

show abstract

Detailed Exploration around 4-Aminoquinolines Chemical Space to Navigate the Lysine Methyltransferase G9a and DNA Methyltransferase Biological Spaces

Cited by 26 publications

References 22 publications

Novel pharmacological maps of protein lysine methyltransferases: key for target deorphanization

Novel pharmacological maps of protein lysine methyltransferases: key for target deorphanization

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

Activity Landscape and Molecular Modeling to Explore the SAR of Dual Epigenetic Inhibitors: A Focus on G9a and DNMT1

Contact Info

Product

Resources

About