Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 144, Issue 41, Pages 18861-18875Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jacs.2c05030
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Funding
- Helmholtz Drug Initiative
- German Cancer Research Center (DKFZ)
- J. Hector Foundation [M91]
- NIH [GM49758]
- University of Pennsylvania Orphan Disease Center Million Dollar Bike Ride [MDBR-20-135-SRS]
- Chan Zuckerberg Initiative
- National Institutes of Health National Cancer Institute [CA204345, CA235863]
- Deutsche Forschungsgemeinschaft (DFG) [SFB 1309, 401883058]
- National Institute of General Medical Sciences from the National Institutes of Health [P30 GM124165]
- DOE Office of Science by Argonne National Laboratory [DE-AC02-06CH11357]
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We report the development of a selective chemical probe DKFZ-748 for HDAC10, demonstrating its potency and selectivity through cellular and biochemical assays. The cocrystal structures of our probe with HDAC10 provide a structural basis for its potency, and chemoproteomic profiling confirms its selectivity across the landscape of HDAC drugs. Treatment with DKFZ-748 validates the suspected cellular function of HDAC10 as a polyamine deacetylase, and its dose-dependent growth inhibition in a polyamine-limiting in vitro tumor model shows its potential as a therapeutic agent.
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.
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