Methyl effect in azumamides provides insight into histone deacetylase inhibition by macrocycles

Alex Ramalak Maolanon; Jesper S. Villadsen; Niels J Christensen; Casper Hoeck; Tina Friis; Pernille Harris; Charlotte Held Gotfredsen; Peter Fristrup; Christian Adam Olsen

doi:10.1021/jm501399d

Methyl effect in azumamides provides insight into histone deacetylase inhibition by macrocycles

Alex Ramalak Maolanon, Jesper S. Villadsen, Niels J Christensen, Casper Hoeck, Tina Friis, Pernille Harris, Charlotte Held Gotfredsen, Peter Fristrup, Christian Adam Olsen

16 Citationer (Scopus)

Abstract

Natural, nonribosomal cyclotetrapeptides have traditionally been a rich source of inspiration for design of potent histone deacetylase (HDAC) inhibitors. We recently disclosed the total synthesis and full HDAC profiling of the naturally occurring azumamides ( J. Med. Chem. 2013 , 56 , 6512 ). In this work, we investigate the structural requirements for potent HDAC inhibition by macrocyclic peptides using the azumamides along with a series of unnatural analogues obtained through chemical synthesis. By solving solution NMR structures of selected macrocycles and combining these findings with molecular modeling, we pinpoint crucial enzyme-ligand interactions required for potent inhibition of HDAC3. Docking of additional natural products confirmed these features to be generally important. Combined with the structural conservation across HDACs 1-3, this suggests that while cyclotetrapeptides have provided potent and class-selective HDAC inhibitors, it will be challenging to distinguish between the three major class I deacetylases using these chemotypes.

Originalsprog	Engelsk
Tidsskrift	Journal of Medicinal Chemistry
Vol/bind	57
Udgave nummer	22
Sider (fra-til)	9644-9657
Antal sider	14
ISSN	0022-2623
DOI	https://doi.org/10.1021/jm501399d
Status	Udgivet - 26 nov. 2014

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title = "Methyl effect in azumamides provides insight into histone deacetylase inhibition by macrocycles",

abstract = "Natural, nonribosomal cyclotetrapeptides have traditionally been a rich source of inspiration for design of potent histone deacetylase (HDAC) inhibitors. We recently disclosed the total synthesis and full HDAC profiling of the naturally occurring azumamides ( J. Med. Chem. 2013 , 56 , 6512 ). In this work, we investigate the structural requirements for potent HDAC inhibition by macrocyclic peptides using the azumamides along with a series of unnatural analogues obtained through chemical synthesis. By solving solution NMR structures of selected macrocycles and combining these findings with molecular modeling, we pinpoint crucial enzyme-ligand interactions required for potent inhibition of HDAC3. Docking of additional natural products confirmed these features to be generally important. Combined with the structural conservation across HDACs 1-3, this suggests that while cyclotetrapeptides have provided potent and class-selective HDAC inhibitors, it will be challenging to distinguish between the three major class I deacetylases using these chemotypes.",

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author = "Maolanon, {Alex Ramalak} and Villadsen, {Jesper S.} and Christensen, {Niels J} and Casper Hoeck and Tina Friis and Pernille Harris and Gotfredsen, {Charlotte Held} and Peter Fristrup and Olsen, {Christian Adam}",

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AU - Maolanon, Alex Ramalak

AU - Villadsen, Jesper S.

AU - Christensen, Niels J

AU - Hoeck, Casper

AU - Friis, Tina

AU - Harris, Pernille

AU - Gotfredsen, Charlotte Held

AU - Fristrup, Peter

AU - Olsen, Christian Adam

PY - 2014/11/26

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N2 - Natural, nonribosomal cyclotetrapeptides have traditionally been a rich source of inspiration for design of potent histone deacetylase (HDAC) inhibitors. We recently disclosed the total synthesis and full HDAC profiling of the naturally occurring azumamides ( J. Med. Chem. 2013 , 56 , 6512 ). In this work, we investigate the structural requirements for potent HDAC inhibition by macrocyclic peptides using the azumamides along with a series of unnatural analogues obtained through chemical synthesis. By solving solution NMR structures of selected macrocycles and combining these findings with molecular modeling, we pinpoint crucial enzyme-ligand interactions required for potent inhibition of HDAC3. Docking of additional natural products confirmed these features to be generally important. Combined with the structural conservation across HDACs 1-3, this suggests that while cyclotetrapeptides have provided potent and class-selective HDAC inhibitors, it will be challenging to distinguish between the three major class I deacetylases using these chemotypes.

AB - Natural, nonribosomal cyclotetrapeptides have traditionally been a rich source of inspiration for design of potent histone deacetylase (HDAC) inhibitors. We recently disclosed the total synthesis and full HDAC profiling of the naturally occurring azumamides ( J. Med. Chem. 2013 , 56 , 6512 ). In this work, we investigate the structural requirements for potent HDAC inhibition by macrocyclic peptides using the azumamides along with a series of unnatural analogues obtained through chemical synthesis. By solving solution NMR structures of selected macrocycles and combining these findings with molecular modeling, we pinpoint crucial enzyme-ligand interactions required for potent inhibition of HDAC3. Docking of additional natural products confirmed these features to be generally important. Combined with the structural conservation across HDACs 1-3, this suggests that while cyclotetrapeptides have provided potent and class-selective HDAC inhibitors, it will be challenging to distinguish between the three major class I deacetylases using these chemotypes.

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KW - Chemistry, Pharmaceutical

KW - Computer Simulation

KW - Crystallography, X-Ray

KW - Drug Design

KW - Drug Evaluation, Preclinical

KW - Histone Deacetylase Inhibitors

KW - Humans

KW - Inhibitory Concentration 50

KW - Kinetics

KW - Ligands

KW - Magnetic Resonance Spectroscopy

KW - Models, Molecular

KW - Peptides, Cyclic

KW - Protein Binding

KW - Protein Conformation

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DO - 10.1021/jm501399d

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C2 - 25380299

SN - 0022-2623

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JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

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ER -

Methyl effect in azumamides provides insight into histone deacetylase inhibition by macrocycles

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