Welcome to the new version of CaltechAUTHORS. Login is currently restricted to library staff. If you notice any issues, please email coda@library.caltech.edu
CaltechAUTHORS
Published November 8, 2018 | Supplemental Material + Published
Journal Article Open

Optimization of Phenyl Indole Inhibitors of the AAA+ ATPase p97

LaPorte, Matthew G.
Burnett, James C.
Colombo, Raffaele
Bulfer, Stacie L. ORCID icon
Alverez, Celeste
Chou, Tsui-Fen ORCID icon
Neitz, R. Jeffrey ORCID icon
Green, Neal ORCID icon
Moore, William J. ORCID icon
Yue, Zhizhou
Li, Shan ORCID icon
Arkin, Michelle R. ORCID icon
Wipf, Peter ORCID icon
Huryn, Donna M. ORCID icon

Abstract

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.

Additional Information

© 2018 American Chemical Society. This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. Received 15 August 2018. Accepted 18 September 2018. Published online 18 September 2018. Published in issue 8 November 2018. The authors gratefully acknowledge Marina Kovaliov (University of Pittsburgh) for technical support and advice; Chaemin Lim (University of Pittsburgh) for data retrieval and collation; Mary Liang (University of Pittsburgh) for compound management and extensive assistance with manuscript preparation; Taber Maskrey (University of Pittsburgh) for analytical chemistry support; Clifford Bryant (UCSF) for preliminary chemistry; Gregory Lee (UCSF) for help with data compilation; Sean Marcsisin, CTP US Army; Jason Sousa and Brittney Potter (WRAIR) for solubility data; AMRI for microsomal stability data; Richard Gussio, CAPT USPHS (NCI) for contributions to computational and molecular modeling studies; and the NCI for access to the NCI-60 cell line. The authors also appreciate the helpful discussion and suggestions of all the CBC p97 project team members, particularly Raymond Deshaies (CalTech), Eric Baldwin (Leidos), Andrew Flint (Leidos), Barbara Mroczowski (NCI), Shizuko Sei (Leidos), Gordon Stott (Leidos), Gunda Georg (University of Minnesota), and Michael Walters (University of Minnesota). 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 approval to the final version of the manuscript. The authors declare no competing financial interest.

Attached Files

Published - acsmedchemlett.8b00372.pdf

Supplemental Material - ml8b00372_si_001.pdf

Files

acsmedchemlett.8b00372.pdf
Files (6.9 MB)
Name Size Download all
md5:7a24e521a1f83ca9f6a408af1d480992
3.3 MB Preview Download
md5:7a9783c338dc45a79e15fedbada23cc1
3.6 MB Preview Download

Additional details

Identifiers Funding Dates
Created:
August 22, 2023
Modified:
October 23, 2023