2. Academic Validation
  3. Aza-SAHA Derivatives Are Selective Histone Deacetylase 10 Chemical Probes That Inhibit Polyamine Deacetylation and Phenocopy HDAC10 Knockout

Aza-SAHA Derivatives Are Selective Histone Deacetylase 10 Chemical Probes That Inhibit Polyamine Deacetylation and Phenocopy HDAC10 Knockout

  • J Am Chem Soc. 2022 Oct 19;144(41):18861-18875. doi: 10.1021/jacs.2c05030.
Raphael R Steimbach 1 2,  Corey J Herbst-Gervasoni 3,  Severin Lechner 4,  Tracy Murray Stewart 5,  Glynis Klinke 6,  Johannes Ridinger 7 8,  Magalie N E Géraldy 1,  Gergely Tihanyi 1,  Jackson R Foley 5,  Ulrike Uhrig 9,  Bernhard Kuster 4,  Gernot Poschet 6,  Robert A Casero Jr 5,  Guillaume Médard 4,  Ina Oehme 7 8 10,  David W Christianson 3,  Nikolas Gunkel 1 11,  Aubry K Miller 1 11
Affiliations

Affiliations

  • 1 Cancer Drug Development, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
  • 2 Biosciences Faculty, Heidelberg University, 69120 Heidelberg, Germany.
  • 3 Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323, United States.
  • 4 Chair of Proteomics and Bioanalytics, Technical University of Munich, 85354 Freising, Germany.
  • 5 Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, United States.
  • 6 Center for Organismal Studies (COS), Heidelberg University, 69120 Heidelberg, Germany.
  • 7 Clinical Cooperation Unit Pediatric Oncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
  • 8 Hopp Children's Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany.
  • 9 Chemical Biology Core Facility, European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany.
  • 10 Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
  • 11 German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
PMID: 36200994 DOI: 10.1021/jacs.2c05030
Abstract

We report the first well-characterized selective chemical probe for histone deacetylase 10 (HDAC10) with unprecedented selectivity over other HDAC isozymes. HDAC10 deacetylates polyamines and has a distinct substrate specificity, making it unique among the 11 zinc-dependent HDAC hydrolases. Taking inspiration from HDAC10 polyamine substrates, we systematically inserted an amino group ("aza-scan") into the hexyl linker moiety of the approved drug Vorinostat (SAHA). This one-atom replacement (C→N) transformed SAHA from an unselective pan-HDAC inhibitor into a specific HDAC10 Inhibitor. Optimization of the aza-SAHA structure yielded the HDAC10 chemical probe DKFZ-748, with potency and selectivity demonstrated by cellular and biochemical target engagement, as well as thermal shift assays. Cocrystal structures of our aza-SAHA derivatives with HDAC10 provide a structural rationale for potency, and chemoproteomic profiling confirmed exquisite cellular HDAC10-selectivity of DKFZ-748 across the target landscape of HDAC drugs. Treatment of cells with DKFZ-748, followed by quantification of selected polyamines, validated for the first time the suspected cellular function of HDAC10 as a polyamine deacetylase. Finally, in a polyamine-limiting in vitro tumor model, DKFZ-748 showed dose-dependent growth inhibition of HeLa cells. We expect DKFZ-748 and related probes to enable further studies on the enigmatic biology of HDAC10 and acetylated polyamines in both physiological and pathological settings.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-151590
    ≥98.0%, HDAC10抑制剂
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