2. Academic Validation
  3. Allosteric Indole Amide Inhibitors of p97: Identification of a Novel Probe of the Ubiquitin Pathway

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.
Celeste Alverez 1,  Stacie L Bulfer 2,  Ramappa Chakrasali 3,  Michael S Chimenti 2,  Raymond J Deshaies 4,  Neal Green 5,  Mark Kelly 2,  Matthew G LaPorte 6,  Taber S Lewis 6,  Mary Liang 1,  William J Moore 5,  R Jeffrey Neitz 2,  Vsevolod A Peshkov 6,  Michael A Walters 3,  Feng Zhang 6,  Michelle R Arkin 2,  Peter Wipf 1,  Donna M Huryn 1
Affiliations

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.
PMID: 26985295 DOI: 10.1021/acsmedchemlett.5b00396
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-124253
    p97 ATP酶抑制剂
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