2. Academic Validation
  3. Characterization of a small molecule inhibitor of disulfide reductases that induces oxidative stress and lethality in lung cancer cells

Characterization of a small molecule inhibitor of disulfide reductases that induces oxidative stress and lethality in lung cancer cells

  • Cell Rep. 2022 Feb 8;38(6):110343. doi: 10.1016/j.celrep.2022.110343.
Fraser D Johnson 1,  John Ferrarone 2,  Alvin Liu 3,  Christina Brandstädter 4,  Ravi Munuganti 5,  Dylan A Farnsworth 6,  Daniel Lu 6,  Jennifer Luu 7,  Tianna Sihota 7,  Sophie Jansen 3,  Amy Nagelberg 7,  Rocky Shi 6,  Giovanni C Forcina 8,  Xu Zhang 9,  Grace S W Cheng 10,  Sandra E Spencer Miko 10,  Georgia de Rappard-Yuswack 3,  Poul H Sorensen 11,  Scott J Dixon 8,  Udayan Guha 9,  Katja Becker 4,  Hakim Djaballah 12,  Romel Somwar 13,  Harold Varmus 2,  Gregg B Morin 14,  William W Lockwood 15
Affiliations

Affiliations

  • 1 Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC, Canada; Interdisciplinary Oncology Program, University of British Columbia, Vancouver, BC, Canada; Canada's Michael Smith Genome Sciences Centre, BC Cancer Research Institute, Vancouver, BC, Canada.
  • 2 Meyer Cancer Centre, Weill Cornell Medicine, New York City, NY, USA.
  • 3 Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC, Canada.
  • 4 Department of Biochemistry and Molecular Biology, Justus Liebig University Giessen, Giessen, Germany.
  • 5 Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
  • 6 Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC, Canada; Interdisciplinary Oncology Program, University of British Columbia, Vancouver, BC, Canada.
  • 7 Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC, Canada; Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
  • 8 Department of Biology, Stanford University, Stanford, CA, USA.
  • 9 Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
  • 10 Canada's Michael Smith Genome Sciences Centre, BC Cancer Research Institute, Vancouver, BC, Canada.
  • 11 Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
  • 12 High Throughput Screening Core Facility, Memorial Sloan-Kettering Cancer Center, New York City, NY, USA; Keren Therapeutics, New York City, NY, USA.
  • 13 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York City, NY, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York City, NY, USA.
  • 14 Canada's Michael Smith Genome Sciences Centre, BC Cancer Research Institute, Vancouver, BC, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
  • 15 Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC, Canada; Interdisciplinary Oncology Program, University of British Columbia, Vancouver, BC, Canada; Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada. Electronic address: [email protected].
PMID: 35139387 DOI: 10.1016/j.celrep.2022.110343
Abstract

Phenotype-based screening can identify small molecules that elicit a desired cellular response, but additional approaches are required to characterize their targets and mechanisms of action. Here, we show that a compound termed LCS3, which selectively impairs the growth of human lung adenocarcinoma (LUAD) cells, induces oxidative stress. To identify the target that mediates this effect, we use thermal proteome profiling (TPP) and uncover the disulfide reductases GSR and TXNRD1 as targets. We confirm through enzymatic assays that LCS3 inhibits disulfide reductase activity through a reversible, uncompetitive mechanism. Further, we demonstrate that LCS3-sensitive LUAD cells are sensitive to the synergistic inhibition of glutathione and thioredoxin pathways. Lastly, a genome-wide CRISPR knockout screen identifies NQO1 loss as a mechanism of LCS3 resistance. This work highlights the ability of TPP to uncover targets of small molecules identified by high-throughput screens and demonstrates the potential therapeutic utility of inhibiting disulfide reductases in LUAD.

Keywords

glutathione; lung cancer; reactive oxygen species; redox homeostasis; small molecule screen; thermal proteome profiling; thioredoxin.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-147328
    98.65%, GSR/TXNRD1 Inhibitor