2. Signaling Pathways
  3. Cell Cycle/DNA Damage
    Epigenetics
  4. HDAC

HDAC

Histone deacetylases

HDAC

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HDAC (Histone deacetylases) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on ahistone, allowing the histones to wrap the DNA more tightly. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. Its action is opposite to that of histone acetyltransferase. HDAC proteins are now also called lysine deacetylases (KDAC), to describe their function rather than their target, which also includes non-histone proteins. Together with the acetylpolyamine amidohydrolases and the acetoin utilization proteins, the histone deacetylases form an ancient protein superfamily known as the histone deacetylase superfamily.

HDAC Isoform Specific Products:

HDAC Isoform Comparison
Cat. No. Product Name Effect Purity Chemical Structure
  • HY-149418
    BChE/HDAC6-IN-2
    		Inhibitor
    BChE/HDAC6-IN-2 (compound 29a) is a dual inhibitor of BChE and HDAC6 with IC50s of 1.8 nM and 71.0 nM, respectively. BChE/HDAC6-IN-2 has prominently neuroprotective effects and reactive oxygen species (ROS) scavenging activity. BChE/HDAC6-IN-2 is also an effective chelator of metal ion (Fe2+ and Cu2+). BChE/HDAC6-IN-2 inhibits phosphorylation of tau, and exhibits moderate immunomodulatory effect.
    BChE/HDAC6-IN-2
  • HY-176733
    HDAC6-IN-61
    		Inhibitor
    HDAC6-IN-61 (Compound 4e) is a HDAC6 inhibitor (IC50: 73 nM) with selectivity over other HDAC isoforms. HDAC6-IN-61 is also a GPR40 activator. HDAC6-IN-61 increases acetylated tubulin and ERK phosphorylation levels. HDAC6-IN-61 can be used for research of neuroinflammation such as Alzheimer's disease.
    HDAC6-IN-61
  • HY-19754A
    CRA-026440 hydrochloride
    		Inhibitor 98.14%
    CRA-026440 hydrochloride is a potent, broad-spectrum HDAC (HDAC) inhibitor. The Ki values against recombinant HDAC isoenzymes HDAC1, HDAC2, HDAC3, HDAC6, HDAC8, and HDAC10 are 4 nM, 14 nM, 11 nM, 15 nM, 7 nM, and 20 nM respectively. CRA-026440 hydrochloride shows antitumor and antiangiogenic activities. CRA-026440 (hydrochloride) is a click chemistry reagent, it contains an Alkyne group and can undergo copper-catalyzed azide-alkyne cycloaddition (CuAAc) with molecules containing Azide groups.
    CRA-026440 hydrochloride
  • HY-169075
    CDK/HDAC-IN-4
    		Inhibitor
    CDK/HDAC-IN-4 is a high selective dual cyclin-dependent kinase (CDK)/histone deacetylase (HDAC) inhibitor with IC50 values of 88.4 and 168.9 nM, respectively. CDK/HDAC-IN-4 exhibits antiproliferative capacities against hematological and solid tumor cells. CDK/HDAC-IN-4 also induces MV-4-11 cell Apoptosis and S cell cycle arrests. CDK/HDAC-IN-4 possesses a significant antitumor potency in the MV-4-11 xenograft model.
    CDK/HDAC-IN-4
  • HY-163846
    HDAC8-IN-10
    		Inhibitor
    HDAC8-IN-10 (compound 15) is a potent inhibitor of HDAC8, with the IC50 of 7.6 nM. HDAC8-IN-10 is a HDAC8 target protein ligand that can be used to synthesize PROTAC YX862 (HY-163845).
    HDAC8-IN-10
  • HY-175021
    HDAC-IN-91
    		Inhibitor
    HDAC-IN-91 is a multiple inhibitor of HDAC (IC50 = 134.22 nM for HDAC1, 66.29 nM for HDAC2), carbonic anhydrase (CA) (Ki = 72.03 nM for CA IX, 50.76 nM for XII), and tubulin polymerization ( IC50 = 2.56 μM). HDAC-IN-91 inhibits PARP1 and increases the Bax/Bcl-2 ratio. HDAC-IN-91 blocks the cell cycle at the G2/M phase and induces apoptosis through a mitochondrial apoptosis activation mechanism. HDAC-IN-91 can exert potent cytotoxic activity through tubulin polymerization inhibition. HDAC-IN-91 can be used in breast, colorectal, cervical and lung cancer research.
    HDAC-IN-91
  • HY-163845
    YX862
    		Degrader
    YX862 is a selective HDAC8 PROTAC degrader and induces the degradation of HDAC8 with maximum degradation ＞ 95% at 250 nM in MDA-MB-231 cells(Sturcture Note:(Blue: VHL E3 ligand (HY-112078), Black: linker；Pink: HDAC8 inhibitor (HY-163846)).
    YX862
  • HY-156016
    HDAC/CD13-IN-1
    HDAC/CD13-IN-1 (Compound 12) is a HDAC/CD13 inhibitor (IC50: 0.34 μM for hCD13, 0.53 μM for porcine CD13, 0.03, 0.06, 0.02 μM for HDAC1/2/3). HDAC/CD13-IN-1 inhibits MV4-11, K562, Jeko-1, and HL60 cell proliferation (IC50: 0.25-2.04 μM). HDAC/CD13-IN-1 induces cancer cell apoptosis. HDAC/CD13-IN-1 has anti-metastasis and anti-invasion efficacy.
    HDAC/CD13-IN-1
  • HY-172159
    FF2039
    		Inhibitor
    FF2039 (compound 1j) is a specific HDAC1, HDAC6, and HDAC isoforms of class I, IIa and IIb PROTAC degrader. FF2039 demonstrates s significant antiproliferative activity against both hematological and solid cancer cell lines, driven by cell cycle arrest and Apoptosis induction. FF2039 inhibits HDAC isoform of HDAC1, HDAC2, HDAC4 and HDAC6 with IC50s of 1.03, 2.15, 12.4 and 0.053 μM, respectively. FF2039 shows antiproliferative activity against different tumor entities of MM.1S, MDA-MB-231 and U-87MG with EC50s of 2.8, 28 and 30 μM, respectively. (Pink: PRMT5 ligand (HY-168864); Blue: E3 ligase ligand HY-W957284); Black: linker (HY-W881439); E3+linker (HY-172185 )).
    FF2039
  • HY-150722
    HDAC6-IN-12
    		Inhibitor
    HDAC6-IN-12 (compound GZ) is a potent HDAC6 inhibitor. HDAC6-IN-12 has anticancer activity through merges into DNA strands causing DNA damage. HDAC6-IN-12 can be used for cancer research.
    HDAC6-IN-12
  • HY-149946
    HDAC-IN-57
    		Inhibitor
    HDAC-IN-57 is an orally active inhibitor of histone deacetylases (HDAC), with IC50s of 2.07 nM, 4.71 nM, 2.4 nM and 107 nM for HDAC1, HDAC2, HDAC6, HDAC8, respectively. HDAC-IN-57 can inhibits LSD1, with IC50 of 1.34 μΜ. HDAC-IN-57 induces apoptosis, and has anti-tumor activity.
    HDAC-IN-57
  • HY-13271AG
    Tubastatin A (GMP)
    		Inhibitor
    Tubastatin A (GMP) is the Tubastatin A (HY-13271A) produced by using GMP guidelines. GMP small molecules work appropriately as an auxiliary reagent for cell therapy manufacture. Tubastatin A is a potent and selective HDAC6 inhibitor with an IC50 of 15 nM in a cell-free assay, and is selective (1000-fold more) against all other isozymes except HDAC8 (57-fold more). Tubastatin A also inhibits HDAC10 and metallo-β-lactamase domain-containing protein 2 (MBLAC2).
    Tubastatin A (GMP)
  • HY-168475
    DD0-2363
    		Inhibitor
    DD0-2363 (Compound 32d) is a dual-target inhibitor of WDR5-MLL1/HDAC. DD0-2363 inhibits cells proliferation and induces apoptosis in acute myeloid leukemia cells. DD0-2363 has antitumor activity and can be used in the research of acute myeloid leukemia.
    DD0-2363
  • HY-144694
    HDAC/HSP90-IN-3
    		Inhibitor
    HDAC/HSP90-IN-3 (compound J5) is a potent and selective fungal Hsp90 and HDAC dual inhibitor, with IC50 values of 0.83 and 0.91 μM, respectively. HDAC/HSP90-IN-3 shows antifungal activity against azole resistant C. albicans. HDAC/HSP90-IN-3 can suppress important virulence factors and down-regulate drug-resistant genes ERG11 and CDR1.
    HDAC/HSP90-IN-3
  • HY-161516
    HDAC6-IN-42
    		Inhibitor
    HDAC6-IN-42 (compound 2b) is an HDAC6 inhibitor (IC50=0.009 μM). HDAC6-IN-42 shows significant anti-leukemia activity and synergistic effect with Decitabine (HY-A0004). HDAC6-IN-42 can be used for the AML research.
    HDAC6-IN-42
  • HY-150503
    KH-259
    		Inhibitor
    KH-259 (compound 1) is a potent, selective and CNS-penetrant HDAC6 inhibitor, with an IC50 of 0.26 μM. KH-259 has antidepressant effects in mice through the inhibition of HDAC6 in the brain. KH-259 can be used for neurodegenerative diseases research.
    KH-259
  • HY-168153
    HDAC-IN-80
    		Inhibitor
    HDAC-IN-80 (compund 5) is a selective class I HDAC inhibitor.
    HDAC-IN-80
  • HY-174302
    PIM-1/HDAC-IN-2
    		Inhibitor
    PIM-1/HDAC-IN-2 is a robust PIM/HDAC inhibitor (IC50 = 0.11 μM in MV4-11cells), which exerts a synergistic antiproliferative effect through a dual mechanism of inhibiting PIM1 kinase and selectively inhibiting HDAC6. PIM-1/HDAC-IN-2 induces cell apoptosis. PIM-1/HDAC-IN-2 remarkably induces the cleavage of PARP, thereby initiating the arrest of the cell cycle in G1 phase and a reduction in S phase. PIM-1/HDAC-IN-2 demonstrates significant anticancer efficacyin the MV4-11 xenograft model without notable toxicity[1].
    PIM-1/HDAC-IN-2
  • HY-19430
    Pimelic Diphenylamide 106 analog
    		Control
    Pimelic Diphenylamide 106 analog is the analog of Pimelic Diphenylamide 106, with unknown activity.
    Pimelic Diphenylamide 106 analog
  • HY-101780A
    Tinostamustine hydrochloride
    		Inhibitor
    Tinostamustine hydrochloride (EDO-S101 hydrochloride) is a compound with anti-multiple myeloma activity and the ability to promote CD38 expression. Tinostamustine hydrochloride enhances the sensitivity of tumor cells to the anti-CD38 monoclonal antibody daratumumab by increasing the acetylation level of histone H3. Tinostamustine hydrochloride can increase the expression of MICA and MICB, thereby activating NK cells. Tinostamustine hydrochloride can significantly delay tumor growth and improve the survival rate of mice.
    Tinostamustine hydrochloride
Cat. No. Product Name / Synonyms Application Reactivity
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Download HDAC Signaling Pathway Map.

TCR, GPCR and HDAC II interaction: Diverse agonists act through G-protein-coupled receptors (GPCRs) to activate the PKC-PKD axis, CaMK, Rho, or MHC binding to antigens stimulates TCR to activate PKD, leading to phosphorylation of class II HDACs. Phospho-HDACs dissociate from MEF2, bind 14-3-3, and are exported to the cytoplasm through a CRM1-dependent mechanism. CRM1 is inhibited by leptomycin B (LMB). Release of MEF2 from class II HDACs allows p300 to dock on MEF2 and stimulate gene expression. Dephosphorylation of class II HDACs in the cytoplasm enables reentry into the nucleus[1].

 

TLR: TLR signaling is initiated by ligand binding to receptors. The recruitment of TLR domain-containing adaptor protein MyD88 is repressed by HDAC6, whereas NF-κB and MTA-1 can be negatively regulated by HDAC1/2/3 and HDAC2, respectively. Acetylation by HATs enhance MKP-1 which inhibits p38-mediated inflammatory responses, while HDAC1/2/3 inhibits MKP-1 activity. HDAC1 and HDAC8 repress, whereas HDAC6 promotes, IRF function in response to viral challenge. HDAC11 inhibits IL-10 expression and HDAC1 and HDAC2 represses IFNγ-dependent activation of the CIITA transcription factor, thus affecting antigen presentation[2][3].

 

IRNAR: IFN-α/β induce activation of the type I IFN receptor and then bring the receptor-associated JAKs into proximity. JAK adds phosphates to the receptor. STATs bind to the phosphates and then phosphorylated by JAKs to form a dimer, leading to nuclear translocation and gene expression. HDACs positively regulate STATs and PZLF to promote antiviral responses and IFN-induced gene expression[2][3].

 

Cell cycle: In G1 phase, HDAC, Retinoblastoma protein (RB), E2F and polypeptide (DP) form a repressor complex. HDAC acts on surrounding chromatin, causing it to adopt a closed chromatin conformation, and transcription is repressed. Prior to the G1-S transition, phosphorylation of RB by CDKs dissociates the repressor complex. Transcription factors (TFs) gain access to their binding sites and, together with the now unmasked E2F activation domain. E2F is then free to activate transcription by contacting basal factors or by contacting histone acetyltransferases, such as CBP, that can alter chromatin structure[4].

 

The function of non-histone proteins is also regulated by HATs/HDACs. p53: HDAC1 impairs the function of p53. p53 is acetylated under conditions of stress or HDAC inhibition by its cofactor CREB binding protein (CBP) and the transcription of genes involved in differentiation is activated. HSP90: HSP90 is a chaperone that complexes with other chaperones, such as p23, to maintain correct conformational folding of its client proteins. HDAC6 deacetylates HSP90. Inhibition of HDAC6 would result in hyperacetylated HSP90, which would be unable to interact with its co-chaperones and properly lead to misfolded client proteins being targeted for degradation via the ubiquitin-proteasome system[5][6].
 

Reference:

[1]. Vega RB, et al. Protein kinases C and D mediate agonist-dependent cardiac hypertrophy through nuclear export of histone deacetylase 5.Mol Cell Biol. 2004 Oct;24(19):8374-85.
[2]. Shakespear MR, et al. Histone deacetylases as regulators of inflammation and immunity. Trends Immunol. 2011 Jul;32(7):335-43.
[3]. Suliman BA, et al. HDACi: molecular mechanisms and therapeutic implications in the innate immune system.Immunol Cell Biol. 2012 Jan;90(1):23-32. 
[4]. Brehm A, et al. Retinoblastoma protein meets chromatin.Trends Biochem Sci. 1999 Apr;24(4):142-5.
[5]. Butler R, et al. Histone deacetylase inhibitors as therapeutics for polyglutamine disorders.Nat Rev Neurosci. 2006 Oct;7(10):784-96
[6]. Minucci S, et al. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer.Nat Rev Cancer. 2006 Jan;6(1):38-51.

HDAC Isoform Comparison

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