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Allosteric Indole Amide Inhibitors of p97: Identification of a Novel Probe of the Ubiquitin Pathway

Alverez, Celeste and Bulfer, Stacie L. and Chakrasali, Ramappa and Chimenti, Michael. S. and Deshaies, Raymond J. and Green, Neal and Kelly, Mark and LaPorte, Matthew G. and Lewis, Taber S. and Liang, Mary and Moore, William J. and Neitz, R. Jeffrey and Peshkov, Vsevolod A. and Walters, Michael A. and Zhang, Feng and Arkin, Michelle R. and Wipf, Peter and Huryn, Donna M. (2016) Allosteric Indole Amide Inhibitors of p97: Identification of a Novel Probe of the Ubiquitin Pathway. ACS Medicinal Chemistry Letters, 7 (2). pp. 182-187. ISSN 1948-5875. https://resolver.caltech.edu/CaltechAUTHORS:20160315-125347072

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Abstract

A high-throughput screen to discover inhibitors of p97 ATPase activity identified an indole amide that bound to an allosteric site of the protein. Medicinal chemistry optimization led to improvements in potency and solubility. Indole amide 3 represents a novel uncompetitive inhibitor with excellent physical and pharmaceutical properties that can be used as a starting point for drug discovery efforts.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1021/acsmedchemlett.5b00396DOIArticle
http://pubs.acs.org/doi/abs/10.1021/acsmedchemlett.5b00396PublisherArticle
http://pubs.acs.org/doi/suppl/10.1021/acsmedchemlett.5b00396Related ItemSupporting Information
ORCID:
AuthorORCID
Deshaies, Raymond J.0000-0002-3671-9354
Additional Information:© 2015 American Chemical Society. Received: October 8, 2015. Accepted: December 22, 2015. Published: December 22, 2015. The authors gratefully acknowledge our colleagues at the University of Pittsburgh Dr. Chaemin Lim for data retrieval, Ms. Shelby Anderson for compound management and handling, and Mr. Peter Chambers for analytical chemistry support; Dr. Tsui-Fen Chou (UCLA) for Ub-GFP reporter assay data on 3, and Dr. Sean Marcsisin, Dr. Jason Sousa and Ms. Brittney Potter (WRAIR) for pharmaceutical property data. The authors also appreciate the helpful discussion and suggestions of all the CBC p97project team members particularly Eric Baldwin (Leidos), Tsui-Fen Chou, Andrew Flint (Leidos), Gunda Georg (University of Minnesota), Matthew P. Jacobson (UCSF), Barbara Mroczowski (NCI), Shizuko Sei (Leidos), and Gordon Stott (Leidos). The project was funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Chemical Biology Consortium Contract No. HHSN261200800001E Agreement No. 29XS127TO15. Author Contributions: The manuscript was written through contributions of all authors. All authors have given final approval to the final version of the manuscript. The authors declare the following competing financial interest(s): Raymond J. Deshaies is co-founder, shareholder, consultant, and member of the SAB of Cleave Biosciences, which is developing p97/VCP inhibitors for clinical use.
Funders:
Funding AgencyGrant Number
National Cancer InstituteHHSN261200800001E
Subject Keywords:AAA ATPase, p97 inhibitor, allosteric inhibitor, indole amide, protein homeostasis, ubiquitin pathway modulator
Issue or Number:2
Record Number:CaltechAUTHORS:20160315-125347072
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20160315-125347072
Official Citation:Allosteric Indole Amide Inhibitors of p97: Identification of a Novel Probe of the Ubiquitin Pathway Celeste Alverez, Stacie L. Bulfer, Ramappa Chakrasali, Michael. S. Chimenti, Raymond J. Deshaies, Neal Green, Mark Kelly, Matthew G. LaPorte, Taber S. Lewis, Mary Liang, William J. Moore, R. Jeffrey Neitz, Vsevolod A. Peshkov, Michael A. Walters, Feng Zhang, Michelle R. Arkin, Peter Wipf, and Donna M. Huryn ACS Medicinal Chemistry Letters 2016 7 (2), 182-187 DOI: 10.1021/acsmedchemlett.5b00396
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:65366
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:15 Mar 2016 23:15
Last Modified:03 Oct 2019 09:46

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