Novel Benzohydroxamate-Based Potent and Selective Histone Deacetylase 6 (HDAC6) Inhibitors Bearing a Pentaheterocyclic Scaffold: Design, Synthesis, and Biological Evaluation

Vergani, Barbara; Sandrone, Giovanni; Marchini, Mattia; Ripamonti, Chiara; Cellupica, Edoardo; Galbiati, Elisabetta; Caprini, G.; Pavich, Gianfranco; Porro, Giulia; Rocchio, Ilaria; Lattanzio, Maria; Pezzuto, Marcello; Skorupska, M.; Cordella, Paola; Pagani, Paolo; Pozzi, Pietro; Pomarico, Roberta; Modena, Daniela; Leoni, Flavio; Perego, Rita; Fossati, Gianluca; Steinkühler, Christian; Stevenazzi, Andrea

doi:10.1021/acs.jmedchem.9b01194

Cited by 41 publications

(34 citation statements)

References 96 publications

(130 reference statements)

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“…Despite its high selectivity reported [36] by Bergman et al., nexturastat A exhibited only a selectivity index of 24 in our HDAC enzyme assays (Table 1). The lower selectivity, compared with the initial selectivity data, is in good agreement with recently published data by Vergani et al [39] …”

Section: Resultssupporting

confidence: 92%

Oxa Analogues of Nexturastat A Demonstrate Improved HDAC6 Selectivity and Superior Antileukaemia Activity

et al. 2021

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The acetylome is important for maintaining the homeostasis of cells. Abnormal changes can result in the pathogenesis of immunological or neurological diseases, and degeneration can promote the manifestation of cancer. In particular, pharmacological intervention in the acetylome with pan‐histone deacetylase (HDAC) inhibitors is clinically validated. However, these drugs exhibit an undesirable risk‐benefit profile due to severe side effects. Selective HDAC inhibitors might promote patient compliance and represent a valuable opportunity in personalised medicine. Therefore, we envisioned the development of HDAC6‐selective inhibitors. During our lead structure identification, we demonstrated that an alkoxyurea‐based connecting unit proves to be beneficial for HDAC6 selectivity and established the synthesis of alkoxyurea‐based hydroxamic acids. Herein, we report highly potent N‐alkoxyurea‐based hydroxamic acids with improved HDAC6 preference compared to nexturastat A. We further validated the biological activity of these oxa analogues of nexturastat A in a broad subset of leukaemia cell lines and demonstrated their superior anti‐proliferative properties compared to nexturastat A.

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Section: Resultssupporting

confidence: 92%

Oxa Analogues of Nexturastat A Demonstrate Improved HDAC6 Selectivity and Superior Antileukaemia Activity

et al. 2021

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“…Vergani and co-workers reported a novel selective HDAC6 inhibitor 17 bearing a tetrazole central core [76]. Remarkably, compound 17 had low toxicity both in vitro and in vivo, confirming selective inhibition of HDAC6 could be well tolerated by healthy cells.…”

Section: Aromatic Hydroxamic Acid-derived Inhibitorsmentioning

confidence: 92%

Recent Advances in Small Molecular Modulators Targeting Histone Deacetylase 6

Xiao

Zhang

2020

Future Drug. Discov.

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Histone deacetylase 6 (HDAC6) is a unique isozyme in the HDAC family with various distinguished characters. HDAC6 is predominantly localized in the cytoplasm and has several specific nonhistone substrates, such as α-tubulin, cortactin, Hsp90, tau and peroxiredoxins. Accumulating evidence reveals that targeting HDAC6 may serve as a promising therapeutic strategy for the treatment of cancers, neurological disorders and immune diseases, making the development of HDAC6 inhibitors particularly attractive. Recently, multitarget drug design and proteolysis targeting chimera technology have also been applied in the discovery of novel small molecular modulators targeting HDAC6. In this review, we briefly describe the structural features and biological functions of HDAC6 and discuss the recent advances in HDAC6 modulators, including selective inhibitors, chimeric inhibitors and proteolysis targeting chimeras for multiple therapeutic purposes.

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“…HDAC6 primarily deacetylates non-histone proteins, including α-tubulin, cortactin, heat shock protein 90 (HSP90), and peroxiredoxin (Prx1) ( Vergani et al, 2019 ; Leyk et al, 2017 ). Histone deacetylase 6 (HDAC6) plays critical role in inflammatory diseases ( Ren et al, 2016 ; Sellmer et al, 2018 ) by regulating the levels of inflammatory cytokines.…”

Section: Introductionmentioning

confidence: 99%

“…HDAC6 primarily deacetylates non-histone proteins, including α-tubulin, cortactin, heat shock protein 90 (HSP90), and peroxiredoxin (Prx1) (Vergani et al, 2019;Leyk et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

HDAC6 and CXCL13 Mediate Atopic Dermatitis by Regulating Cellular Interactions and Expression Levels of miR-9 and SIRT1

et al. 2021

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Histone deacetylase 6 (HDAC6) has been known to regulate inflammatory diseases. The role of HDAC6 in allergic skin inflammation has not been studied. We studied the role of HDAC6 in atopic dermatitis (AD) and the mechanisms associated with it. The decreased expression or chemical inhibition of HDAC6 suppressed AD by decreasing autophagic flux and cellular features of AD. AD increased expression levels of the Th1 and Th2 cytokines, but decreased expression levels of forkhead box P3 (FoxP3) and interleukin-10 (IL-10) in an HDAC6-dependent manner. CXC chemokine ligand 13 (CXCL13), which was increased in an HDAC6-depenednt manner, mediated AD. MiR-9, negatively regulated by HDAC6, suppressed AD by directly regulating the expression of sirtuin 1 (SIRT1). The downregulation or inhibition of SIRT1 suppressed AD. Experiments employing culture medium and transwell suggested that cellular interactions involving mast cells, keratinocytes, and dermal fibroblast cells could promote AD; HDAC6 and CXCL13 were found to be necessary for these cellular interactions. Mouse recombinant CXCL13 protein increased HDAC6 expression in skin mast cells and dermal fibroblast cells. CXCL13 protein was found to be present in the exosomes of DNCB-treated skin mast cells. Exosomes of DNCB-treated skin mast cells enhanced invasion potentials of keratinocytes and dermal fibroblast cells and increased expression levels of HDAC6, SIRT1 and CXCL13 in keratinocytes and dermal fibroblast cells. These results indicate that HDAC6 and CXCL13 may serve as targets for the developing anti-atopic drugs.

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Novel Benzohydroxamate-Based Potent and Selective Histone Deacetylase 6 (HDAC6) Inhibitors Bearing a Pentaheterocyclic Scaffold: Design, Synthesis, and Biological Evaluation

Cited by 41 publications

References 96 publications

Oxa Analogues of Nexturastat A Demonstrate Improved HDAC6 Selectivity and Superior Antileukaemia Activity

Oxa Analogues of Nexturastat A Demonstrate Improved HDAC6 Selectivity and Superior Antileukaemia Activity

Recent Advances in Small Molecular Modulators Targeting Histone Deacetylase 6

HDAC6 and CXCL13 Mediate Atopic Dermatitis by Regulating Cellular Interactions and Expression Levels of miR-9 and SIRT1

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