Optimization of Phenyl Indole Inhibitors of the AAA+ ATPase p97

[Image: see text] Optimization of the side-chain of a phenyl indole scaffold identified from a high-throughput screening campaign for inhibitors of the AAA+ ATPase p97 is reported. The addition of an N-alkyl piperazine led to high potency of this series in a biochemical assay, activity in cell-based...

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Autores principales: LaPorte, Matthew G., Burnett, James C., Colombo, Raffaele, Bulfer, Stacie L., Alverez, Celeste, Chou, Tsui-Fen, Neitz, R. Jeffrey, Green, Neal, Moore, William J., Yue, Zhizhou, Li, Shan, Arkin, Michelle R., Wipf, Peter, Huryn, Donna M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2018
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6231190/
https://www.ncbi.nlm.nih.gov/pubmed/30429948
http://dx.doi.org/10.1021/acsmedchemlett.8b00372
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author LaPorte, Matthew G.
Burnett, James C.
Colombo, Raffaele
Bulfer, Stacie L.
Alverez, Celeste
Chou, Tsui-Fen
Neitz, R. Jeffrey
Green, Neal
Moore, William J.
Yue, Zhizhou
Li, Shan
Arkin, Michelle R.
Wipf, Peter
Huryn, Donna M.
author_facet LaPorte, Matthew G.
Burnett, James C.
Colombo, Raffaele
Bulfer, Stacie L.
Alverez, Celeste
Chou, Tsui-Fen
Neitz, R. Jeffrey
Green, Neal
Moore, William J.
Yue, Zhizhou
Li, Shan
Arkin, Michelle R.
Wipf, Peter
Huryn, Donna M.
author_sort LaPorte, Matthew G.
collection PubMed
description [Image: see text] Optimization of the side-chain of a phenyl indole scaffold identified from a high-throughput screening campaign for inhibitors of the AAA+ ATPase p97 is reported. The addition of an N-alkyl piperazine led to high potency of this series in a biochemical assay, activity in cell-based assays, and excellent pharmaceutical properties. Molecular modeling based on a subsequently obtained cryo-EM structure of p97 in complex with a phenyl indole was used to rationalize the potency of these allosteric inhibitors.
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spelling pubmed-62311902018-11-14 Optimization of Phenyl Indole Inhibitors of the AAA+ ATPase p97 LaPorte, Matthew G. Burnett, James C. Colombo, Raffaele Bulfer, Stacie L. Alverez, Celeste Chou, Tsui-Fen Neitz, R. Jeffrey Green, Neal Moore, William J. Yue, Zhizhou Li, Shan Arkin, Michelle R. Wipf, Peter Huryn, Donna M. ACS Med Chem Lett [Image: see text] Optimization of the side-chain of a phenyl indole scaffold identified from a high-throughput screening campaign for inhibitors of the AAA+ ATPase p97 is reported. The addition of an N-alkyl piperazine led to high potency of this series in a biochemical assay, activity in cell-based assays, and excellent pharmaceutical properties. Molecular modeling based on a subsequently obtained cryo-EM structure of p97 in complex with a phenyl indole was used to rationalize the potency of these allosteric inhibitors. American Chemical Society 2018-09-18 /pmc/articles/PMC6231190/ /pubmed/30429948 http://dx.doi.org/10.1021/acsmedchemlett.8b00372 Text en Copyright © 2018 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
spellingShingle LaPorte, Matthew G.
Burnett, James C.
Colombo, Raffaele
Bulfer, Stacie L.
Alverez, Celeste
Chou, Tsui-Fen
Neitz, R. Jeffrey
Green, Neal
Moore, William J.
Yue, Zhizhou
Li, Shan
Arkin, Michelle R.
Wipf, Peter
Huryn, Donna M.
Optimization of Phenyl Indole Inhibitors of the AAA+ ATPase p97
title Optimization of Phenyl Indole Inhibitors of the AAA+ ATPase p97
title_full Optimization of Phenyl Indole Inhibitors of the AAA+ ATPase p97
title_fullStr Optimization of Phenyl Indole Inhibitors of the AAA+ ATPase p97
title_full_unstemmed Optimization of Phenyl Indole Inhibitors of the AAA+ ATPase p97
title_short Optimization of Phenyl Indole Inhibitors of the AAA+ ATPase p97
title_sort optimization of phenyl indole inhibitors of the aaa+ atpase p97
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6231190/
https://www.ncbi.nlm.nih.gov/pubmed/30429948
http://dx.doi.org/10.1021/acsmedchemlett.8b00372
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