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; Donna M Huryn

doi:10.1021/acsmedchemlett.5b00396

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

ACS Med Chem Lett. 2015 Dec 22;7(2):182-7. doi: 10.1021/acsmedchemlett.5b00396. eCollection 2016 Feb 11.

Authors

Celeste Alverez¹, Stacie L Bulfer², Ramappa Chakrasali³, Michael S Chimenti², Raymond J Deshaies⁴, Neal Green⁵, Mark Kelly², Matthew G LaPorte⁶, Taber S Lewis⁶, Mary Liang¹, William J Moore⁵, R Jeffrey Neitz², Vsevolod A Peshkov⁶, Michael A Walters³, Feng Zhang⁶, Michelle R Arkin², Peter Wipf¹, Donna M Huryn¹

Affiliations

¹ Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States; University of Pittsburgh Chemical Diversity Center, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States.
² Department of Pharmaceutical Chemistry, Small Molecule Discovery Center, University of California , San Francisco, California 94158, United States.
³ Department of Medicinal Chemistry, and the Institute for Therapeutics Discovery and Development, University of Minnesota , Minneapolis, Minnesota 55414, United States.
⁴ Division of Biology and Biological Engineering, California Institute of Technology and Howard Hughes Medical Institute , Pasadena, California 91007, United States.
⁵ Leidos Biomedical Research, Inc. , Frederick, Maryland 21702, United States.
⁶ University of Pittsburgh Chemical Diversity Center, University of Pittsburgh , Pittsburgh, Pennsylvania 15260, United States.

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.

Keywords: AAA ATPase; allosteric inhibitor; indole amide; p97 inhibitor; protein homeostasis; ubiquitin pathway modulator.