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Identification of Pirin as a Molecular Target of the CCG-1423/CCG-203971 Series of Antifibrotic and Antimetastatic Compounds

  • Erika M. Lisabeth
    Erika M. Lisabeth
    Department of Pharmacology & Toxicology, Michigan State University, East Lansing, Michigan, 48824, United States
  • Dylan Kahl
    Dylan Kahl
    Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan, 48109, United States
    More by Dylan Kahl
  • Indiwari Gopallawa
    Indiwari Gopallawa
    Department of Pharmacology & Toxicology, Michigan State University, East Lansing, Michigan, 48824, United States
  • Sarah E. Haynes
    Sarah E. Haynes
    Department of Chemistry, University of Michigan, Ann Arbor, Michigan, 48109, United States
  • Sean A. Misek
    Sean A. Misek
    Department of Pharmacology & Toxicology, Michigan State University, East Lansing, Michigan, 48824, United States
  • Phillip L. Campbell
    Phillip L. Campbell
    Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, Michigan, 48109, United States
  • Thomas S. Dexheimer
    Thomas S. Dexheimer
    Department of Pharmacology & Toxicology, Michigan State University, East Lansing, Michigan, 48824, United States
  • Dinesh Khanna
    Dinesh Khanna
    Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, Michigan, 48109, United States
  • David A. Fox
    David A. Fox
    Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, Michigan, 48109, United States
    More by David A. Fox
  • Xiangshu Jin
    Xiangshu Jin
    Department of Biochemistry, Michigan State University, East Lansing, Michigan, 48824, United States
    More by Xiangshu Jin
  • Brent R. Martin
    Brent R. Martin
    Department of Chemistry, University of Michigan, Ann Arbor, Michigan, 48109, United States
  • Scott D. Larsen
    Scott D. Larsen
    Department of Medicinal Chemistry  and  Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, 48109, United States
  • , and 
  • Richard R. Neubig*
    Richard R. Neubig
    Department of Pharmacology & Toxicology, Michigan State University, East Lansing, Michigan, 48824, United States
    *E-mail: [email protected]
Cite this: ACS Pharmacol. Transl. Sci. 2019, 2, 2, 92–100
Publication Date (Web):March 18, 2019
https://doi.org/10.1021/acsptsci.8b00048
Copyright © 2019 American Chemical Society

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    Abstract

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    A series of compounds (including CCG-1423 and CCG-203971) discovered through an MRTF/SRF-dependent luciferase screen has shown remarkable efficacy in a variety of in vitro and in vivo models, including significant reduction of melanoma metastasis and bleomycin-induced fibrosis. Although these compounds are efficacious in these disease models, the molecular target is unknown. Here, we describe affinity isolation-based target identification efforts which yielded pirin, an iron-dependent cotranscription factor, as a target of this series of compounds. Using biophysical techniques including isothermal titration calorimetry and X-ray crystallography, we verify that pirin binds these compounds in vitro. We also show with genetic approaches that pirin modulates MRTF-dependent luciferase reporter activity. Finally, using both siRNA and a previously validated pirin inhibitor, we show a role for pirin in TGF-β-induced gene expression in primary dermal fibroblasts. A recently developed analog, CCG-257081, which cocrystallizes with pirin, is also effective in the prevention of bleomycin-induced dermal fibrosis.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsptsci.8b00048.

    • Coomassie gel of recombinant His-pirin, CCG-257081 bound pirin is similar to inactive pirin, CCG-222740 and CCT251236 have minimal effects on recombinant luciferase activity, pirin mRNA is reduced in siPirin primary dermal fibroblasts, CCG-203971 does not disrupt the MRTFA-RPEL:actin interaction, CCG compounds and pirin affect the TGF-β signaling pathway, exemplary probe development SAR, data collection and refinement statistics, overlap between CCG-1423 and siPirin microarray gene sets, intersection between CCG-1423 and MRTF gene signatures, materials and methods (PDF)

    • Proteomic results, gene signatures tested and overlap with CCG-1423 gene signature (XLSX)

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    Cited By

    This article is cited by 24 publications.

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    21. Jip Zonderland, Silvia Rezzola, Lorenzo Moroni. Actomyosin and the MRTF-SRF pathway downregulate FGFR1 in mesenchymal stromal cells. Communications Biology 2020, 3 (1) https://doi.org/10.1038/s42003-020-01309-1
    22. Alexa C. Cannon, Cristina Uribe-Alvarez, Jonathan Chernoff. RAC1 as a Therapeutic Target in Malignant Melanoma. Trends in Cancer 2020, 6 (6) , 478-488. https://doi.org/10.1016/j.trecan.2020.02.021
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