title: Allosteric Indole Amide Inhibitors of p97: Identification of a Novel Probe of the Ubiquitin Pathway.
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.
authors.affiliation: 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.
authors.forename: Celeste
authors.initials: C
authors.lastname: Alverez
authors.affiliation: Department of Pharmaceutical Chemistry, Small Molecule Discovery Center, University of California , San Francisco, California 94158, United States.
authors.forename: Stacie L
authors.initials: SL
authors.lastname: Bulfer
authors.affiliation: Department of Medicinal Chemistry, and the Institute for Therapeutics Discovery and Development, University of Minnesota , Minneapolis, Minnesota 55414, United States.
authors.forename: Ramappa
authors.initials: R
authors.lastname: Chakrasali
authors.affiliation: Department of Pharmaceutical Chemistry, Small Molecule Discovery Center, University of California , San Francisco, California 94158, United States.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Chimenti
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology and Howard Hughes Medical Institute , Pasadena, California 91007, United States.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Deshaies
authors.affiliation: Leidos Biomedical Research, Inc. , Frederick, Maryland 21702, United States.
authors.forename: Neal
authors.initials: N
authors.lastname: Green
authors.affiliation: Department of Pharmaceutical Chemistry, Small Molecule Discovery Center, University of California , San Francisco, California 94158, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Kelly
authors.affiliation: University of Pittsburgh Chemical Diversity Center, University of Pittsburgh , Pittsburgh, Pennsylvania 15260, United States.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: LaPorte
authors.affiliation: University of Pittsburgh Chemical Diversity Center, University of Pittsburgh , Pittsburgh, Pennsylvania 15260, United States.
authors.forename: Taber S
authors.initials: TS
authors.lastname: Lewis
authors.affiliation: 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.
authors.forename: Mary
authors.initials: M
authors.lastname: Liang
authors.affiliation: Leidos Biomedical Research, Inc. , Frederick, Maryland 21702, United States.
authors.forename: William J
authors.initials: WJ
authors.lastname: Moore
authors.affiliation: Department of Pharmaceutical Chemistry, Small Molecule Discovery Center, University of California , San Francisco, California 94158, United States.
authors.forename: R Jeffrey
authors.initials: RJ
authors.lastname: Neitz
authors.affiliation: University of Pittsburgh Chemical Diversity Center, University of Pittsburgh , Pittsburgh, Pennsylvania 15260, United States.
authors.forename: Vsevolod A
authors.initials: VA
authors.lastname: Peshkov
authors.affiliation: Department of Medicinal Chemistry, and the Institute for Therapeutics Discovery and Development, University of Minnesota , Minneapolis, Minnesota 55414, United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Walters
authors.affiliation: University of Pittsburgh Chemical Diversity Center, University of Pittsburgh , Pittsburgh, Pennsylvania 15260, United States.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutical Chemistry, Small Molecule Discovery Center, University of California , San Francisco, California 94158, United States.
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Arkin
authors.affiliation: 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.
authors.forename: Peter
authors.initials: P
authors.lastname: Wipf
authors.affiliation: 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.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Huryn
keywords: AAA ATPase; allosteric inhibitor; indole amide; p97 inhibitor; protein homeostasis; ubiquitin pathway modulator