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Synthesis and functional screening of novel inhibitors targeting the HDAC6 zinc finger ubiquitin-binding domain

Silke Geurs (UGent) , Eleni Staessens (UGent) , Kato Bredael (UGent) , Stefaan Borghgraef, Jordy De Ridder, Leentje Persoons, Steven De Jonghe, Dominique Schols, Mandeep K. Mann, Rachel J. Harding, et al.
(2025) EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. 285.
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Abstract
Histone deacetylase 6 (HDAC6) is a promising target for treating neurodegenerative disorders, several cancer types and viral infections. Unique among HDACs, the HDAC6 isoform possesses a zinc finger ubiquitin-binding domain (UBD) crucial for managing misfolded protein aggregates and facilitating viral infection. HDAC6 binds aggregated polyubiquitinated proteins through its UBD, mediating their transport to the aggresome and subsequent removal via autophagy. Despite the importance of the UBD in proteostasis and viral infection, its pharmacological inhibition has been minimally explored thus far, with research largely focused on the deacetylase domain. We synthesized a diverse library of new compounds designed to target the HDAC6-UBD, termed HZUBi, with varied core structures including quinazolinone, oxindole and tetrahydrothiopyrano[4,3-b]indole, aimed at enhancing UBD interaction and extending into the side pocket. New structure-activity relationships were established, computational docking and molecular dynamics studies were performed and the functional impact of selected inhibitors was assessed in the context of multiple myeloma and viral infection. Several new HZUBi could displace a ubiquitin peptide from HDAC6-UBD in a differential manner, although to a lower extent than the literature reference compound HZUBi-3e. Despite exhibiting in vitro target engagement, neither HZUBi-3e nor its ester prodrug HZUBi-1e enhanced proteasome inhibitor-mediated multiple myeloma cell killing. Finally, none of the screened HZUBi triggered anti-viral activity.
Keywords
Histone deacetylase 6 (HDAC6), HDAC6 ubiquitin-binding domain, Aggresome, Multiple myeloma, Antiviral activity, HISTONE DEACETYLASE 6, REGULATES AGGRESOME FORMATION, PROTEASOME INHIBITORS, MULTIPLE-MYELOMA, PROTEIN, STRESS, POLYUBIQUITIN, DEGRADATION, BORTEZOMIB, AUTOPHAGY

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Citation

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MLA
Geurs, Silke, et al. “Synthesis and Functional Screening of Novel Inhibitors Targeting the HDAC6 Zinc Finger Ubiquitin-Binding Domain.” EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 285, 2025, doi:10.1016/j.ejmech.2024.117208.
APA
Geurs, S., Staessens, E., Bredael, K., Borghgraef, S., De Ridder, J., Persoons, L., … D’hooghe, M. (2025). Synthesis and functional screening of novel inhibitors targeting the HDAC6 zinc finger ubiquitin-binding domain. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 285. https://doi.org/10.1016/j.ejmech.2024.117208
Chicago author-date
Geurs, Silke, Eleni Staessens, Kato Bredael, Stefaan Borghgraef, Jordy De Ridder, Leentje Persoons, Steven De Jonghe, et al. 2025. “Synthesis and Functional Screening of Novel Inhibitors Targeting the HDAC6 Zinc Finger Ubiquitin-Binding Domain.” EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 285. https://doi.org/10.1016/j.ejmech.2024.117208.
Chicago author-date (all authors)
Geurs, Silke, Eleni Staessens, Kato Bredael, Stefaan Borghgraef, Jordy De Ridder, Leentje Persoons, Steven De Jonghe, Dominique Schols, Mandeep K. Mann, Rachel J. Harding, Jorick Franceus, Tom Desmet, Kristof Van Hecke, Dorien Clarisse, Karolien De Bosscher, and Matthias D’hooghe. 2025. “Synthesis and Functional Screening of Novel Inhibitors Targeting the HDAC6 Zinc Finger Ubiquitin-Binding Domain.” EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 285. doi:10.1016/j.ejmech.2024.117208.
Vancouver
1.
Geurs S, Staessens E, Bredael K, Borghgraef S, De Ridder J, Persoons L, et al. Synthesis and functional screening of novel inhibitors targeting the HDAC6 zinc finger ubiquitin-binding domain. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. 2025;285.
IEEE
[1]
S. Geurs et al., “Synthesis and functional screening of novel inhibitors targeting the HDAC6 zinc finger ubiquitin-binding domain,” EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 285, 2025.
@article{01JJ21Z8NENYG6BJRQ57XJFDDC,
  abstract     = {{Histone deacetylase 6 (HDAC6) is a promising target for treating neurodegenerative disorders, several cancer types and viral infections. Unique among HDACs, the HDAC6 isoform possesses a zinc finger ubiquitin-binding domain (UBD) crucial for managing misfolded protein aggregates and facilitating viral infection. HDAC6 binds aggregated polyubiquitinated proteins through its UBD, mediating their transport to the aggresome and subsequent removal via autophagy. Despite the importance of the UBD in proteostasis and viral infection, its pharmacological inhibition has been minimally explored thus far, with research largely focused on the deacetylase domain. We synthesized a diverse library of new compounds designed to target the HDAC6-UBD, termed HZUBi, with varied core structures including quinazolinone, oxindole and tetrahydrothiopyrano[4,3-b]indole, aimed at enhancing UBD interaction and extending into the side pocket. New structure-activity relationships were established, computational docking and molecular dynamics studies were performed and the functional impact of selected inhibitors was assessed in the context of multiple myeloma and viral infection. Several new HZUBi could displace a ubiquitin peptide from HDAC6-UBD in a differential manner, although to a lower extent than the literature reference compound HZUBi-3e. Despite exhibiting in vitro target engagement, neither HZUBi-3e nor its ester prodrug HZUBi-1e enhanced proteasome inhibitor-mediated multiple myeloma cell killing. Finally, none of the screened HZUBi triggered anti-viral activity.}},
  articleno    = {{117208}},
  author       = {{Geurs, Silke and Staessens, Eleni and Bredael, Kato and Borghgraef, Stefaan and De Ridder, Jordy and Persoons, Leentje and De Jonghe, Steven and Schols, Dominique and Mann, Mandeep K. and Harding, Rachel J. and Franceus, Jorick and Desmet, Tom and Van Hecke, Kristof and Clarisse, Dorien and De Bosscher, Karolien and D'hooghe, Matthias}},
  issn         = {{0223-5234}},
  journal      = {{EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY}},
  keywords     = {{Histone deacetylase 6 (HDAC6),HDAC6 ubiquitin-binding domain,Aggresome,Multiple myeloma,Antiviral activity,HISTONE DEACETYLASE 6,REGULATES AGGRESOME FORMATION,PROTEASOME INHIBITORS,MULTIPLE-MYELOMA,PROTEIN,STRESS,POLYUBIQUITIN,DEGRADATION,BORTEZOMIB,AUTOPHAGY}},
  language     = {{eng}},
  pages        = {{26}},
  title        = {{Synthesis and functional screening of novel inhibitors targeting the HDAC6 zinc finger ubiquitin-binding domain}},
  url          = {{http://doi.org/10.1016/j.ejmech.2024.117208}},
  volume       = {{285}},
  year         = {{2025}},
}
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