HDAC6 Inhibitor
(Synonyms: Histone Deacetylase 6) 目录号 : GC41085
An inhibitor of HDAC6
Cas No.:1259296-46-2
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
HDAC6 is a predominantly cytoplasmic enzyme that targets α-tubulin, cortactin, and heat shock protein 90, as well as other substrates. In this way, it impacts development, proliferation, invasion, and tumorigenesis. HDAC6 Inhibitor is a potent and selective inhibitor of HDAC6 (IC50 = 36 nM) that poorly blocks other HDAC enzymes. It is cell permeable, inhibiting the acetylation of tubulin in cells with an IC50 value of 210 nM.
| Cas No. | 1259296-46-2 | SDF | |
| 别名 | Histone Deacetylase 6 | ||
| Canonical SMILES | O=C(NO)C1=CC(CCN(C(C2=CC=CN2C)=O)C3)=C3C=C1 | ||
| 分子式 | C16H17N3O3 | 分子量 | 299.3 |
| 溶解度 | DMF: 30 mg/ml,DMSO: 30 mg/ml,Ethanol: 30 mg/ml | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.3411 mL | 16.7056 mL | 33.4113 mL |
| 5 mM | 0.6682 mL | 3.3411 mL | 6.6823 mL |
| 10 mM | 0.3341 mL | 1.6706 mL | 3.3411 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
An HDAC6 Inhibitor reverses chemotherapy-induced mechanical hypersensitivity via an IL-10 and macrophage dependent pathway
Brain Behav Immun 2022 Feb;100:287-296.PMID:34915156DOI:10.1016/j.bbi.2021.12.005.
Chemotherapy-induced peripheral neuropathy (CIPN) impacts a growing number of cancer survivors and treatment options are limited. Histone deacetylase 6 (HDAC6) inhibitors are attractive candidates because they reverse established CIPN and may enhance anti-tumor effects of chemotherapy. Before considering clinical application of HDAC6 inhibitors, the mechanisms underlying reversal of CIPN need to be identified. We showed previously that deletion of Hdac6 from sensory neurons did not prevent cisplatin-induced mechanical hypersensitivity, while global deletion of Hdac6 was protective, indicating involvement of HDAC6 in other cell types. Here we show that local depletion of MRC1 (CD206)-positive macrophages without affecting microglia by intrathecal administration of mannosylated clodronate liposomes reduced the capacity of an HDAC6 Inhibitor to reverse cisplatin-induced mechanical hypersensitivity. The HDAC6 Inhibitor increased spinal cord Il10 mRNA and this was M2-macrophage dependent. Intrathecal administration of anti-IL-10 antibody or genetic deletion of Il10 prevented resolution of mechanical hypersensitivity. Genetic deletion of the IL-10 receptor from Advillin+ neurons prevented resolution of mechanical hypersensitivity in mice treated with the HDAC6 Inhibitor. These findings indicate that treatment with an HDAC6 Inhibitor increases macrophage-derived IL-10 signaling to IL-10 receptors on Advillin+ sensory neurons to resolve mechanical hypersensitivity. Cisplatin decreases mitochondrial function in sensory axons, and HDAC6 inhibition can promote axonal transport of healthy mitochondria. Indeed, the HDAC6 Inhibitor normalized cisplatin-induced tibial nerve mitochondrial deficits. However, this was independent of macrophages and IL-10 signaling. In conclusion, our findings indicate that administration of an HDAC6 Inhibitor reverses cisplatin-induced mechanical hypersensitivity through two complementary pathways: macrophage HDAC6 inhibition to promote IL-10 production and IL-10 signaling to DRG neurons, and neuronal HDAC6 inhibition to restore axonal mitochondrial health.
Discovery of HDAC6-Selective Inhibitor NN-390 with in Vitro Efficacy in Group 3 Medulloblastoma
J Med Chem 2022 Feb 24;65(4):3193-3217.PMID:35119267DOI:10.1021/acs.jmedchem.1c01585.
Histone deacetylase 6 (HDAC6) has been targeted in clinical studies for anticancer effects due to its role in oncogenic transformation and metastasis. Through a second-generation structure-activity relationship (SAR) study, the design, and biological evaluation of the selective HDAC6 Inhibitor NN-390 is reported. With nanomolar HDAC6 potency, >200-550-fold selectivity for HDAC6 in analogous HDAC isoform functional assays, potent intracellular target engagement, and robust cellular efficacy in cancer cell lines, NN-390 is the first HDAC6-selective inhibitor to show therapeutic potential in metastatic Group 3 medulloblastoma (MB), an aggressive pediatric brain tumor often associated with leptomeningeal metastases and therapy resistance. MB stem cells contribute to these patients' poor clinical outcomes. NN-390 selectively targets this cell population with a 44.3-fold therapeutic margin between patient-derived Group 3 MB cells in comparison to healthy neural stem cells. NN-390 demonstrated a 45-fold increased potency over HDAC6-selective clinical candidate citarinostat. In summary, HDAC6-selective molecules demonstrated in vitro therapeutic potential against Group 3 MB.
Characterization of a new small-molecule inhibitor of HDAC6 in glioblastoma
Cell Death Dis 2020 Jun 2;11(6):417.PMID:32488056DOI:10.1038/s41419-020-2586-x.
Histone deacetylase 6 (HDAC6) is an epigenetic modifier that is an attractive pharmacological target in cancer. In this work, we show that HDAC6 is elevated in glioblastoma, the most malignant and common brain tumor in adults, in which its high levels correlate with poor patient survival and is more abundant in glioma stem cell subpopulation. Moreover, we identified a new small-molecule inhibitor of HDAC6, which presents strong sensitivity for HDAC6 inhibition and exerts high cytotoxic activity, alone or in combination with temozolomide. It is also able to significantly reduce tumor growth in vivo. Transcriptomic analysis of patient-derived glioma stem cells revealed an increase in cell differentiation and cell death pathways, as well as a decrease in cell-cycle activity and cell division by the treatment with the compound. Finally, the comparison with a pan-HDAC inhibitor, Vorinostat (SAHA), or HDAC6-specific inhibitor, Tubastatin A, showed higher target specificity and antitumor activity of the new HDAC6 Inhibitor. In conclusion, our data reveal the efficacy of a novel HDAC6 Inhibitor in glioblastoma preclinical setting.
HDAC6 Inhibitor, ACY1215 suppress the proliferation and induce apoptosis of gallbladder cancer cells and increased the chemotherapy effect of gemcitabine and oxaliplatin
Drug Dev Res 2021 Jun;82(4):598-604.PMID:33428788DOI:10.1002/ddr.21780.
As an anti-tumor agent, histone deacetylases (HDACs) inhibitors have attracted wide attention. ACY1215 is a highly effective selective inhibitor of HDAC6, which can inhibit many kinds of tumors. Whether the expression of HDAC6 and its new inhibitor ACY1215 can inhibit the proliferation of gallbladder cancer cells and induce their apoptosis remains to be further studied. The purpose of this study was to explore the effects of ACY1215 on the gallbladder cancer cells. Cell proliferation of GBC-SD and SGC-996 was assessed by cell counting kit-8 assay and colony formation assay. Flow cytometry was used to detect the apoptosis of gallbladder cancer cells. Western blot was used to detect the expressions of PCNA，KI67, and apoptosis-related proteins of gallbladder cancer cells. The HDAC6 Inhibitor ACY1215 suppressed the proliferation of GBC-SD and SDC-996 cells and promoted the apoptosis of gallbladder cancer cells. The HDAC6 Inhibitor ACY1215 increases the chemotherapy effect of gemcitabine and oxaliplatin. ACY1215 could suppress cell proliferation and induce apoptosis of GBC-SD and SGC-996, and increased the chemotherapy effect of gemcitabine and oxaliplatin, which provides a rationale for the combination of HDAC6 selective inhibitors with other anticancer agents in treating gallbladder cancer.
HDAC6 Inhibitor ACY-1215 improves neuropathic pain and its comorbidities in rats of peripheral nerve injury by regulating neuroinflammation
Chem Biol Interact 2022 Feb 1;353:109803.PMID:34998817DOI:10.1016/j.cbi.2022.109803.
The fact that neuropathic pain (NP) has no effective therapy and is frequently accompanied by psychiatric comorbidities is well established. Aberrant neuroinflammation plays an important role in the development and maintenance of NP. HDAC6 inhibitors have been demonstrated to ameliorate mechanical allodynia brought on by chemotherapy and peripheral nerve damage. However, its pharmacological mechanisms and its effects on NP-related mental disorders have not been fully elucidated. The present study was dedicated to exploring the effects of ACY-1215 (a specific HDAC6 Inhibitor) on neuroinflammation and behavioral abnormalities associated with NP. In this work, spinal nerve ligation (SNL) was performed as an NP model on rats. Mechanical allodynia, cognitive impairment, and depressive-like behavior caused by SNL were attenuated by continuous intraperitoneal injection of ACY-1215. Moreover, ACY-1215 administration suppressed SNL-induced neuroinflammatory responses (including microgliosis, the elevation of pro-inflammatory factors IL-1β and TNF-α) in ligation of the ipsilateral spinal dorsal horn (iSDH), hippocampus (HPC) and prefrontal cortex (PFC). Mechanistically, MyD88-dependent pro-inflammatory pathways (MyD88/NF-κB and MyD88/ERK) were activated in the iSDH following SNL and were inhibited by ACY-1215. Moreover, ACY-1215 enhanced the acetylation modification of MyD88 and inhibited the SNL-induced elevation of MyD88 without affecting its transcription in the iSDH. These findings suggest that pharmacological inhibition of HDAC6 can ameliorate NP and its psychiatric complications through modulating neuroinflammation, in part by blocking the MyD88-mediated pro-inflammatory pathways. The possible mechanism is that ACY-1215 prevents the elevation of MyD88 reactivity by increasing its acetylation level. Notably, neither SNL nor ACY-1215 significantly altered MyD88 expression in HPC and PFC, indicating differentiated pro-inflammatory mechanisms in the supraspinal neural regions.