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
  • 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.

Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-151590
    DKFZ-748
    98.98%, HDAC10 Inhibitor
    target: HDAC
    Research Areas: Cancer