Structure-Based Inhibitor Discovery of Class I Histone Deacetylases (HDACs)

Luo, Yuxiang; Li, Huilin

doi:10.3390/ijms21228828

Cited by 33 publications

(22 citation statements)

References 168 publications

(295 reference statements)

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“…Inhibitors of FLT3-ITD and HDACi are known to cause cell cycle arrest (Li et al 2020 ; Luo and Li 2020 ; Majothi et al 2020 ; Marensi et al 2021 ; Scholl et al 2020 ). FK228 induced p21 and cell cycle arrest in G2/M phase.…”

Section: Discussionmentioning

confidence: 99%

“…It is unclear whether a pharmacological inhibition of individual classes of HDACs can interact favorably with specific TKi against leukemic cells with aberrant FLT3 activation. Due to the strong association between class I HDACs and tumor growth and development (Li et al 2020 ; Luo and Li 2020 ), these could be good targets for such an approach. Class I HDACi with reported anticancer activity are the clinically tested entinostat (MS-275), the neurologically used drug valproic acid, and the experimental agents RGFP966 and MERCK60 (Beyer et al 2019 ; Blaheta and Cinatl 2002 ; Krämer 2009 ; Lakshmaiah et al 2014 ).…”

Section: Introductionmentioning

confidence: 99%

“…HDACi with a specific inhibitory profile against individual HDACs produce less side effects than pan-HDACi (Li et al 2020 ; Luo and Li 2020 ; Müller and Krämer 2010 ) and could therefore be a good combination partner with FLT3i. We treated AML cells that carry FLT3-ITD with AC220 and HDACi.…”

Section: Introductionmentioning

confidence: 99%

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Inhibitors of class I HDACs and of FLT3 combine synergistically against leukemia cells with mutant FLT3

et al. 2021

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Acute myeloid leukemia (AML) with mutations in the FMS-like tyrosine kinase (FLT3) is a clinically unresolved problem. AML cells frequently have a dysregulated expression and activity of epigenetic modulators of the histone deacetylase (HDAC) family. Therefore, we tested whether a combined inhibition of mutant FLT3 and class I HDACs is effective against AML cells. Low nanomolar doses of the FLT3 inhibitor (FLT3i) AC220 and an inhibition of class I HDACs with nanomolar concentrations of FK228 or micromolar doses of the HDAC3 specific agent RGFP966 synergistically induce apoptosis of AML cells that carry hyperactive FLT3 with an internal tandem duplication (FLT3-ITD). This does not occur in leukemic cells with wild-type FLT3 and without FLT3, suggesting a preferential toxicity of this combination against cells with mutant FLT3. Moreover, nanomolar doses of the new FLT3i marbotinib combine favorably with FK228 against leukemic cells with FLT3-ITD. The combinatorial treatments potentiated their suppressive effects on the tyrosine phosphorylation and stability of FLT3-ITD and its downstream signaling to the kinases ERK1/ERK2 and the inducible transcription factor STAT5. The beneficial pro-apoptotic effects of FLT3i and HDACi against leukemic cells with mutant FLT3 are associated with dose- and drug-dependent alterations of cell cycle distribution and DNA damage. This is linked to a modulation of the tumor-suppressive transcription factor p53 and its target cyclin-dependent kinase inhibitor p21. While HDACi induce p21, AC220 suppresses the expression of p53 and p21. Furthermore, we show that both FLT3-ITD and class I HDAC activity promote the expression of the checkpoint kinases CHK1 and WEE1, thymidylate synthase, and the DNA repair protein RAD51 in leukemic cells. A genetic depletion of HDAC3 attenuates the expression of such proteins. Thus, class I HDACs and hyperactive FLT3 appear to be valid targets in AML cells with mutant FLT3.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inhibitors of class I HDACs and of FLT3 combine synergistically against leukemia cells with mutant FLT3

et al. 2021

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“…The enzymatic activity of class I, class II, and class IV HDACs depends on Zn 2+ ions. In contrast, Class III enzymatic activity depends on nicotinamide adenine dinucleotide (NAD) + levels [ 11 , 12 ]. For this review, we will further describe only HDAC classes I, II, and IV, and discuss the growing evidence for their roles in SC biology and nerve regeneration.…”

Section: Histone Deacetylases (Hdacs)mentioning

confidence: 99%

Emerging Role of HDACs in Regeneration and Ageing in the Peripheral Nervous System: Repair Schwann Cells as Pivotal Targets

Gomez-Sanchez

Patel

Martirena

et al. 2022

IJMS

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The peripheral nervous system (PNS) has a remarkable regenerative capacity in comparison to the central nervous system (CNS), a phenomenon that is impaired during ageing. The ability of PNS axons to regenerate after injury is due to Schwann cells (SC) being reprogrammed into a repair phenotype called Repair Schwann cells. These repair SCs are crucial for supporting axonal growth after injury, myelin degradation in a process known as myelinophagy, neurotropic factor secretion, and axonal growth guidance through the formation of Büngner bands. After regeneration, repair SCs can remyelinate newly regenerated axons and support nonmyelinated axons. Increasing evidence points to an epigenetic component in the regulation of repair SC gene expression changes, which is necessary for SC reprogramming and regeneration. One of these epigenetic regulations is histone acetylation by histone acetyl transferases (HATs) or histone deacetylation by histone deacetylases (HDACs). In this review, we have focused particularly on three HDAC classes (I, II, and IV) that are Zn2+-dependent deacetylases. These HDACs are important in repair SC biology and remyelination after PNS injury. Another key aspect explored in this review is HDAC genetic compensation in SCs and novel HDAC inhibitors that are being studied to improve nerve regeneration.

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“…Thus, approaches aimed at designing selective inhibitors are widely desirable to address off-target and adverse effects of HDAC inhibitors [ 15 ]. Structural requirements for the design of selective HDAC inhibitors have been described elsewhere [ 16 , 17 , 18 , 19 , 20 , 21 ]. In general, the scaffold of an HDAC inhibitor is constituted by a zinc-binding group, a hydrophobic linker, and an exposure “cap” ( Figure 2 ).…”

Section: Introductionmentioning

confidence: 99%

Optimization of Resveratrol Used as a Scaffold to Design Histone Deacetylase (HDAC-1 and HDAC-2) Inhibitors

et al. 2022

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Histone deacetylases (HDAC) are epigenetic enzymes responsible for repressing gene expression through the deacetylation of histone lysine residues. Therefore, inhibition of HDACs has become an interesting approach for the treatment of several diseases, including cancer, hematology, neurodegenerative, immune diseases, bacterial infections, and more. Resveratrol (RVT) has pleiotropic effects, including pan-inhibition of HDAC isoforms; however, its ability to interfere with membranes requires additional optimization to eliminate nonspecific and off-target effects. Thus, to explore RVT as a scaffold, we designed a series of novel HDAC-1 and -2 inhibitors containing the 2-aminobenzamide subunit. Using molecular modeling, all compounds, except unsaturated compounds (4) and (7), exhibited a similar mode of interaction at the active sites of HDAC 1 and 2. The docking score values obtained from the study ranged from −12.780 to −10.967 Kcal/mol. All compounds were synthesized, with overall yields ranging from 33% to 67.3%. In an initial screening, compounds (4), (5), (7), and (20)–(26), showed enzymatic inhibitory effects ranging from 1 to 96% and 6 to 93% against HDAC-1 and HDAC-2, respectively. Compound (5), the most promising HDAC inhibitor in this series, was selected for IC50 assays, resulting in IC50 values of 0.44 µM and 0.37 µM against HDAC-1 and HDAC-2, respectively. In a panel of selectivity against HDACs 3–11, compound (5) presented selectivity towards Class I, mainly HDAC-1, 2, and 3. All compounds exhibited suitable physicochemical and ADMET properties as determined using in silico simulations. In conclusion, the optimization of the RVT structure allows the design of selective HDAC inhibitors, mainly targeting HDAC-1 and HDAC-2 isoforms.

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Structure-Based Inhibitor Discovery of Class I Histone Deacetylases (HDACs)

Cited by 33 publications

References 168 publications

Inhibitors of class I HDACs and of FLT3 combine synergistically against leukemia cells with mutant FLT3

Inhibitors of class I HDACs and of FLT3 combine synergistically against leukemia cells with mutant FLT3

Emerging Role of HDACs in Regeneration and Ageing in the Peripheral Nervous System: Repair Schwann Cells as Pivotal Targets

Optimization of Resveratrol Used as a Scaffold to Design Histone Deacetylase (HDAC-1 and HDAC-2) Inhibitors

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