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Development of Multifunctional Histone Deacetylase 6 Degraders with Potent Antimyeloma Activity

  • Hao Wu
    Hao Wu
    School of Pharmacy, University of Wisconsin—Madison, Madison, Wisconsin 53705, United States
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  • , 
  • Ka Yang
    Ka Yang
    School of Pharmacy, University of Wisconsin—Madison, Madison, Wisconsin 53705, United States
    More by Ka Yang
    Orcidhttp://orcid.org/0000-0001-8937-7397
  • , 
  • Zhongrui Zhang
    Zhongrui Zhang
    School of Pharmacy  and  Department of Chemistry, University of Wisconsin—Madison, Madison, Wisconsin 53705, United States
    More by Zhongrui Zhang
  • , 
  • Eric D. Leisten
    Eric D. Leisten
    School of Pharmacy, University of Wisconsin—Madison, Madison, Wisconsin 53705, United States
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  • , 
  • Ziyuan Li
    Ziyuan Li
    School of Pharmacy, University of Wisconsin—Madison, Madison, Wisconsin 53705, United States
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  • , 
  • Haibo Xie
    Haibo Xie
    School of Pharmacy, University of Wisconsin—Madison, Madison, Wisconsin 53705, United States
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  • , 
  • Jin Liu
    Jin Liu
    School of Pharmacy, University of Wisconsin—Madison, Madison, Wisconsin 53705, United States
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  • , 
  • Kerry A. Smith
    Kerry A. Smith
    School of Pharmacy, University of Wisconsin—Madison, Madison, Wisconsin 53705, United States
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  • , 
  • Zora Novakova
    Zora Novakova
    Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV, Prumyslova 595, 252 50 Vestec, Czech Republic
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    Orcidhttp://orcid.org/0000-0001-9804-6346
  • , 
  • Cyril Barinka
    Cyril Barinka
    Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV, Prumyslova 595, 252 50 Vestec, Czech Republic
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    Orcidhttp://orcid.org/0000-0003-2751-3060
  • , and 
  • Weiping Tang*
    Weiping Tang
    School of Pharmacy  and  Department of Chemistry, University of Wisconsin—Madison, Madison, Wisconsin 53705, United States
    *E-mail: [email protected]
    More by Weiping Tang
    Orcidhttp://orcid.org/0000-0002-0039-3196
Cite this: J. Med. Chem. 2019, 62, 15, 7042–7057
Publication Date (Web):July 4, 2019
https://doi.org/10.1021/acs.jmedchem.9b00516
Copyright © 2019 American Chemical Society
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    Abstract

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    Histone deacetylase 6 (HDAC6) primarily catalyzes the removal of acetyl group from the side chain of acetylated lysine residues in cytoplasmic proteins such as α-tubulin and HSP90. HDAC6 is involved in multiple disease-relevant pathways. Based on the proteolysis targeting chimera strategy, we previously developed the first HDAC6 degrader by tethering a pan-HDAC inhibitor with cereblon (CRBN) E3 ubiquitin ligase ligand. We herein report our new generation of multifunctional HDAC6 degraders by tethering selective HDAC6 inhibitor Nexturastat A with CRBN ligand that can synergize with HDAC6 degradation for the antiproliferation of multiple myeloma (MM). This new class of degraders exhibited improved potency and selectivity for the degradation of HDAC6. After the optimization of the linker length and linking positions, we discovered potent HDAC6 degraders with nanomolar DC50 and promising antiproliferation activity in multiple myeloma (MM) cells.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.9b00516.

    • List of primers for qRT-PCR; statistical significance of Figure 7B; validation of in-cell ELISA; full western blots of Figures 5A,B and 6B and wash-out experiment; an additional western blot analysis of proteins in A431, RPMI8226, Jurkat, HepG2, RS4;11, A375, MCF-7 cell lines treated with 12d or 12n; qRT-PCR assays with 12d; western blots of deactivated degraders 13 and 15, and an apoptosis assay with 12d; 1H and 13C NMR spectra of compounds 4a–e, 11a–e, 12a–r, 13, 14, and 15; LC–MS spectra of 12a–r, 13, and 15 (PDF)

    • Molecular string files for all of the final target compounds (CSV)

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