Published February 11, 2016
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Journal Article
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Allosteric Indole Amide Inhibitors of p97: Identification of a Novel Probe of the Ubiquitin Pathway
- Creators
- Alverez, Celeste
- Bulfer, Stacie L.
- Chakrasali, Ramappa
- Chimenti, Michael. S.
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Deshaies, Raymond J.
- Green, Neal
- Kelly, Mark
- LaPorte, Matthew G.
- Lewis, Taber S.
- Liang, Mary
- Moore, William J.
- Neitz, R. Jeffrey
- Peshkov, Vsevolod A.
- Walters, Michael A.
- Zhang, Feng
- Arkin, Michelle R.
- Wipf, Peter
- Huryn, Donna M.
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.
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.Attached Files
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Additional details
- Eprint ID
- 65366
- Resolver ID
- CaltechAUTHORS:20160315-125347072
- HHSN261200800001E
- National Cancer Institute
- Created
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2016-03-15Created from EPrint's datestamp field
- Updated
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2021-11-10Created from EPrint's last_modified field