Improved Selective Class I HDAC and Novel Selective HDAC3 Inhibitors: Beyond Hydroxamic Acids and Benzamides

Bresciani, Alberto; Ontoria, Jesus M.; Biancofiore, Ilaria; Cellucci, Antonella; Ciammaichella, A; Marco, Annalise Di; Ferrigno, Federica; Francone, Alessandra; Malancona, Savina; Monteagudo, Edith; Nizi, Emanuela; Pace, Paola; Ponzi, Simona; Rossetti, Ilaria; Veneziano, Maria; Summa, Vincenzo; Harper, Steven J.

doi:10.1021/acsmedchemlett.8b00517

Cited by 28 publications

(30 citation statements)

References 23 publications

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“…While HDACi effects on GF activation require further characterization with regards to the involvement of epigenetic and non epigenetic mechanisms, and should be studied in detail also in gingival epithelial cells ( Yin and Chung 2011 ), the results presented here provide strong evidence that HDAC3 acts as a crucial regulator of inflammatory mediator expression. Our data suggest that HDACi, in particular selective HDAC3 inhibitors ( Bresciani et al 2019 ), may ameliorate the excessive inflammatory response of gingival cells to periodontal pathogens, and their application could be clinically beneficial as an adjunct to the conventional treatment of periodontitis.…”

Section: Discussionmentioning

confidence: 88%

HDAC3 Regulates Gingival Fibroblast Inflammatory Responses in Periodontitis

et al. 2019

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Histone deacetylases (HDACs) are important regulators of gene expression that are aberrantly regulated in several inflammatory and infectious diseases. HDAC inhibitors (HDACi) suppress inflammatory activation of various cell types through epigenetic and non-epigenetic mechanisms, and ameliorate pathology in a mouse model of periodontitis. Activation of gingival fibroblasts (GFs) significantly contributes to the development of periodontitis and the anaerobic bacterium Porphyromonas gingivalis plays a key role in driving chronic inflammation. Here, we analyzed the role of HDACs in inflammatory responses of GFs. Pan-HDACi suberoylanilide hydroxamic acid (SAHA) and/or ITF2357 (givinostat) significantly reduced TNFα- and P. gingivalis–inducible expression and/or production of a cluster of inflammatory mediators in healthy donor GFs ( IL1B, CCL2, CCL5, CXCL10, COX2, and MMP3) without affecting cell viability. Selective inhibition of HDAC3/6, but not specific HDAC1, HDAC6, or HDAC8 inhibition, reproduced the suppressive effects of pan-HDACi on the inflammatory gene expression profile induced by TNFα and P. gingivalis, suggesting a critical role for HDAC3 in GF inflammatory activation. Consistently, silencing of HDAC3 expression with siRNA largely recapitulated the effects of HDAC3/6i on mRNA levels of inflammatory mediators in P. gingivalis–infected GFs. In contrast, P. gingivalis internalization and intracellular survival in GFs remained unaffected by HDACi. Activation of mitogen-activated protein kinases and NFκB signaling was unaffected by global or HDAC3/6-selective HDACi, and new protein synthesis was not required for gene suppression by HDACi. Finally, pan-HDACi and HDAC3/6i suppressed P. gingivalis–induced expression of IL1B, CCL2, CCL5, CXCL10, MMP1, and MMP3 in GFs from patients with periodontitis. Our results identify HDAC3 as an important regulator of inflammatory gene expression in GFs and suggest that therapeutic targeting of HDAC activity, in particular HDAC3, may be clinically beneficial in suppressing inflammation in periodontal disease.

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Section: Discussionmentioning

confidence: 88%

HDAC3 Regulates Gingival Fibroblast Inflammatory Responses in Periodontitis

et al. 2019

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“…Fetal bovine serum, penicillin/streptomycin, glutamine, HEPES, fungizone, deoxyribonuclease I, and Hoechst 33342 were from Invitrogen (Thermo Fisher, Monza Italy Fluorescein isothiocyanate-labelled FITC-dextran 40, dimethyl sulfoxide (DMSO), lucifer yellow, rhodamine-123, kynurenic acid, elacridar (GF120918), Y-27632 (ROCK inhibitor), and triton X100 were purchased from Sigma-Aldrich, Milan, Italy, and 8% paraformaldehyde aqueous solution was from Electron Microscopy Sciences (Hatfield, PA, USA). CHDI compounds, denoted cp (A to J) and histone deacetylase (HDAC) inhibitor (cp K) were synthesized as previously described [10,11].…”

Section: Reagentsmentioning

confidence: 99%

“…We tested in our model a class I selective human HDAC inhibitor (CpK, Figure 7B), a preclinical development candidate that demonstrated proof-of-concept in an mdx mouse model for Duchenne muscular dystrophy and previously profiled in the porcine model [10]. This 2-methoxyquinoline derivative showed a medium permeability in both models, although the MPO score (a drug likeness central nervous system multiparameter optimization) is less than 3.8, slightly lower than the cut-off of 4 for probable permeable compound.…”

Section: Drug Candidates Permeability Measured In Hipsc-bmecsmentioning

confidence: 99%

Establishment of an in Vitro Human Blood-Brain Barrier Model Derived from Induced Pluripotent Stem Cells and Comparison to a Porcine Cell-Based System

Marco

Vignone

Paz

et al. 2020

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The blood-brain barrier (BBB) is responsible for the homeostasis between the cerebral vasculature and the brain and it has a key role in regulating the influx and efflux of substances, in healthy and diseased states. Stem cell technology offers the opportunity to use human brain-specific cells to establish in vitro BBB models. Here, we describe the establishment of a human BBB model in a two-dimensional monolayer culture, derived from human induced pluripotent stem cells (hiPSCs). This model was characterized by a transendothelial electrical resistance (TEER) higher than 2000 Ω∙cm2 and associated with negligible paracellular transport. The hiPSC-derived BBB model maintained the functionality of major endothelial transporter proteins and receptors. Some proprietary molecules from our central nervous system (CNS) programs were evaluated revealing comparable permeability in the human model and in the model from primary porcine brain endothelial cells (PBECs).

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“…Regardless of the clinical success, the present trend in this field is equally aligned towards the development of both the classes of inhibitors. An obvious explanation to this is the evidenced susceptibility of hydroxamic acids to glucuronide conjugation leading to inactivation and off-targeting whereas some explorations reported that aminoanilides are less prone to glucuronide metabolism and are endowed with high efficacy possibly due to their slow, tight binding and slow disassembling with HDACs [190,191,[363][364][365][366][367][368]. Another notable variation between the two classes can be observed in their enzymatic inhibitory profile as pan HDAC inhibition and selective HDAC 6 inhibition is mostly exerted via use of hydroxamic acid based HDAC inhibitors while class I HDAC selectivity is usually attained via the fabrication of aminoanilides.…”

Section: Isoform Selective Inhibitors: Employing a Structural Template To Furnish Selective Isoform Inhibitors Of The Enzymesmentioning

confidence: 99%

Recent developments in epigenetic cancer therapeutics: clinical advancement and emerging trends

2021

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Epigenetic drug discovery field has evidenced significant advancement in the recent times. A plethora of small molecule inhibitors have progressed to clinical stage investigations and are being explored exhaustively to ascertain conclusive benefits in diverse malignancies. Literature precedents indicates that substantial amount of efforts were directed towards the use of epigenetic tools in monotherapy as well as in combination regimens at the clinical level, however, the preclinical/preliminary explorations were inclined towards the identification of prudent approaches that can leverage the anticancer potential of small molecule epigenetic inhibitors as single agents only. This review article presents an update of FDA approved epigenetic drugs along with the epigenetic inhibitors undergoing clinical stage investigations in different cancer types. A detailed discussion of the pragmatic strategies that are expected to steer the progress of the epigenetic therapy through the implementation of emerging approaches such as PROTACS and CRISPR/Cas9 along with logical ways for scaffold fabrication to selectively approach the enzyme isoforms in pursuit of garnering amplified antitumor effects has been covered. In addition, the compilation also presents the rational strategies for the construction of multi-targeting scaffold assemblages employing previously identified pharmacophores as potential alternatives to the combination therapy.

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Improved Selective Class I HDAC and Novel Selective HDAC3 Inhibitors: Beyond Hydroxamic Acids and Benzamides

Cited by 28 publications

References 23 publications

HDAC3 Regulates Gingival Fibroblast Inflammatory Responses in Periodontitis

HDAC3 Regulates Gingival Fibroblast Inflammatory Responses in Periodontitis

Establishment of an in Vitro Human Blood-Brain Barrier Model Derived from Induced Pluripotent Stem Cells and Comparison to a Porcine Cell-Based System

Recent developments in epigenetic cancer therapeutics: clinical advancement and emerging trends

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