Tucidinostat
(Synonyms: 西达本胺; Chidamide; HBI-8000; CS 055) 目录号 : GC37845
Tucidinostat，也称为Chidamide或CS055/HBI-8000，是HDAC1、HDAC2、HDAC3和HDAC10的抑制剂，IC50值分别为95 nM、160 nM、67 nM和78 nM。
Cas No.:1616493-44-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
Cell lines | K562 cells |
Preparation Method | Cells were exposed to Tucidinostat treatment, and subsequent cell proliferation rates were quantitatively assessed. |
Reaction Conditions | 0.25, 0.5, 1, 2, 4 and 8uM; 24, 48, 72 and 96h |
Applications | Tucidinostat showed a dose-dependent and time-dependent inhibition of K562 cell proliferation. |
| Animal experiment [2]: | |
Animal models | Female BALB/c–nude mice(SKM-1 leukemia model) |
Preparation Method | Mice were divided into two groups randomly. One group received oral administration of Tucidinostat at a dose of 25 mg/kg of body weight, Tucidinostat dissolved in 0.2% carboxymethyl cellulose and 0.1% Tween 80 (200 μl). The other group was orally administered 1% DMSO three times weekly for a duration of 2 weeks. |
Dosage form | 25 mg/kg; p.o; thrice weekly for 2 weeks |
Applications | Tucidinostat effectively suppresses the proliferation of acute myeloid leukemia cells in vivo. Following Tucidinostat treatment, a notable reduction in tumor size was observed. |
References: [1]:Liang S, Zhou X, et,al. Chidamide Inhibits Cell Proliferation via the PI3K/AKT Pathway in K562 Cells Based on Network Pharmacology and Experimental Validation. Curr Pharm Des. 2021;27(26):2990-2998. doi: 10.2174/1381612827666210701152250. PMID: 34218775. [2]:Liang S, Zhou X, et,al. Chidamide Inhibits Cell Proliferation via the PI3K/AKT Pathway in K562 Cells Based on Network Pharmacology and Experimental Validation. Curr Pharm Des. 2021;27(26):2990-2998. doi: 10.2174/1381612827666210701152250. PMID: 34218775. | |
Tucidinostat, also known as Chidamide or CS055/HBI-8000, is an inhibitor of HDAC1, HDAC2, HDAC3, and HDAC10, with IC50 values of 95 nM, 160 nM, 67 nM, and 78 nM, respectively. It belongs to the benzamide class of selective HDAC inhibitors and is capable of promoting histone H3 acetylation. Tucidinostat has demonstrated efficacy in inhibiting tumor growth across a range of malignant tumors[1-2].
Tucidinostat(0.25-8uM; 24-96h) inhibited the proliferation of K562 cells in a dose- and time-dependent manner. It achieved this by blocking cells in the G0/G1 phase through downregulation of cyclin-dependent kinase 4 (CDK4). Additionally, Tucidinostat induced apoptosis by upregulating Bax and downregulating Bcl-2[3]. Tucidinostat(0.1-6uM ;72 h) elicited growth inhibition and cell cycle arrest in rituximab-resistant B-cell lymphoma cell lines (RRCL) [4]. Tucidinostat(0, 2.5, and 10 μM; 48 h) significantly upregulated E-cadherin expression in TGF-β-treated cells and suppressed the migration of lung cancer cells[5].
Tucidinostat(25 mg/kg; p.o; thrice weekly for 2 weeks) inhibited the formation of subcutaneous leukemia tumors. Following treatment with Tucidinostat, the tumor size was significantly reduced[6]. Tucidinostat, at a dosage of 5 mg/kg, combined with fluzoparib, more significantly inhibited neoplasm growth compared to monotherapy[7].
[1]. Ning ZQ, Li ZB, et al. Chidamide (CS055/HBI-8000): a new histone deacetylase inhibitor of the benzamide class with antitumor activity and the ability to enhance immune cell-mediated tumor cell cytotoxicity. Cancer Chemother Pharm. 2012;69:901–9.
[2]. Liu L, Chen B, et al. A novel histone deacetylase inhibitor Chidamide induces apoptosis of human colon cancer cells. Biochem Biophys Res Commun. 2010 Feb 5;392(2):190-5. doi: 10.1016/j.bbrc.2010.01.011. Epub 2010 Jan 7. PMID: 20060381.
[3]. Liang S, Zhou X, et al. Chidamide Inhibits Cell Proliferation via the PI3K/AKT Pathway in K562 Cells Based on Network Pharmacology and Experimental Validation. Curr Pharm Des. 2021;27(26):2990-2998. doi: 10.2174/1381612827666210701152250. PMID: 34218775.
[4]. Xue K, Wu JC, et al. Chidamide triggers BTG1-mediated autophagy and reverses the chemotherapy resistance in the relapsed/refractory B-cell lymphoma. Cell Death Dis. 2021 Oct 1;12(10):900. doi: 10.1038/s41419-021-04187-5. PMID: 34599153; PMCID: PMC8486747.
[5]. Lin SH, Wang BY, et al. Chidamide alleviates TGF-β-induced epithelial-mesenchymal transition in lung cancer cell lines. Mol Biol Rep. 2016 Jul;43(7):687-95. doi: 10.1007/s11033-016-4005-z. Epub 2016 May 17. PMID: 27188428.
[6]. Xue K, Wu JC, et al. Chidamide triggers BTG1-mediated autophagy and reverses the chemotherapy resistance in the relapsed/refractory B-cell lymphoma. Cell Death Dis. 2021 Oct 1;12(10):900. doi: 10.1038/s41419-021-04187-5. PMID: 34599153; PMCID: PMC8486747.
[7]. Li X, Yuan X, et al. Chidamide Reverses Fluzoparib Resistance in Triple-Negative Breast Cancer Cells. Front Oncol. 2022 Feb 18;12:819714. doi: 10.3389/fonc.2022.819714. PMID: 35251986; PMCID: PMC8894594.
Tucidinostat，也称为Chidamide或CS055/HBI-8000，是HDAC1、HDAC2、HDAC3和HDAC10的抑制剂，IC50值分别为95 nM、160 nM、67 nM和78 nM。它属于苯甲酰胺类选择性HDAC抑制剂，能够促进组蛋白H3乙酰化。Tucidinostat已被证明对多种恶性肿瘤具有抑制肿瘤生长的功效[1-2]。
Tucidinostat(0.25-8uM; 24-96h) 对K562细胞的增殖具有剂量依赖性和时间依赖性。它下调细胞周期蛋白依赖性激酶4 (CDK4)阻断G0/G1期的细胞。此外，Tucidinostat通过上调Bax和下调Bcl-2诱导细胞凋亡[3]。在利妥昔单抗耐药b细胞淋巴瘤细胞系(RRCL)中，Tucidinostat(0.1-6uM;72 h)可引起生长抑制和细胞周期阻滞[4]。Tucidinostat(0、2.5、10 μM);48 h)显著上调TGF-β处理细胞中E-cadherin的表达，抑制肺癌细胞的迁移[5]。
Tucidinostat(25 mg/kg; p.o; thrice weekly for 2 weeks)抑制皮下白血病肿瘤的形成，应用Tucidinostat治疗后，肿瘤大小明显减小[6]。与单药治疗相比，5 mg/kg剂量的途西替他与氟唑帕尼联用能更显著地抑制肿瘤生长[7]。
| Cas No. | 1616493-44-7 | SDF | |
| 别名 | 西达本胺; Chidamide; HBI-8000; CS 055 | ||
| Canonical SMILES | O=C(C1=CC=C(CNC(/C=C/C2=CN=CC=C2)=O)C=C1)NC(C=CC(F)=C3)=C3N | ||
| 分子式 | C22H19FN4O2 | 分子量 | 390.41 |
| 溶解度 | DMSO: ≥ 50 mg/mL (128.07 mM) | 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 | 2.5614 mL | 12.807 mL | 25.6141 mL |
| 5 mM | 0.5123 mL | 2.5614 mL | 5.1228 mL |
| 10 mM | 0.2561 mL | 1.2807 mL | 2.5614 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 | ||||||||||
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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。
Oral histone deacetylase inhibitor Tucidinostat (HBI-8000) in patients with relapsed or refractory adult T-cell leukemia/lymphoma: Phase IIb results
Cancer Sci 2022 Aug;113(8):2778-2787.PMID:35579212DOI:10.1111/cas.15431.
This multicenter, prospective phase IIb trial evaluating the efficacy and safety of Tucidinostat (HBI-8000) in patients with relapsed or refractory (R/R) adult T-cell leukemia/lymphoma (ATLL) was undertaken in Japan. Eligible patients had R/R ATLL and had failed standard of care treatment with chemotherapy and with mogamulizumab. Twenty-three patients received Tucidinostat 40 mg orally twice per week and were included in efficacy and safety analyses. The primary end-point was objective response rate (ORR) assessed by an independent committee. The ORR was 30.4% (95% confidence interval [CI], 13.2, 52.9]. Median progression-free survival was 1.7 months (95% CI, 0.8, 7.4), median duration of response was 9.2 months (95% CI, 2.6, not reached), and median overall survival was 7.9 months (95% CI, 2.3, 18.0). All patients experienced adverse events (AEs), which were predominantly hematologic and gastrointestinal. Incidence of grade 3 or higher AEs was 78.3%; most were laboratory abnormalities (decreases in platelets, neutrophils, white blood cells, and hemoglobin). Tucidinostat was well tolerated with AEs that could be mostly managed with supportive care and dose modifications. Tucidinostat is a meaningful treatment option for R/R ATLL patients; further investigation is warranted.
Therapeutic potential of Tucidinostat, a subtype-selective HDAC inhibitor, in cancer treatment
Front Pharmacol 2022 Sep 2;13:932914.PMID:36120308DOI:10.3389/fphar.2022.932914.
Histone deacetylase (HDAC) is one of the most characterized epigenetic modifiers, modulating chromatin structure and gene expression, which plays an important role in cell cycle, differentiation and apoptosis. Dysregulation of HDAC promotes cancer progression, thus inhibitors targeting HDACs have evidently shown therapeutic efficacy in multiple cancers. Tucidinostat (formerly known as chidamide), a novel subtype-selective HDAC inhibitor, inhibits Class I HDAC1, HDAC2, HDAC3, as well as Class IIb HDAC10. Tucidinostat is approved in relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL), advanced breast cancer and R/R adult T-cell leukemia-lymphoma (ATLL). Compared with other HDAC inhibitors, Tucidinostat shows notable antitumor activity, remarkable synergistic effect with immunotherapy, and manageable toxicity. Here, we comprehensively summarize recent advances in Tucidinostat as both monotherapy and a regimen of combination therapy in both hematological and solid malignancies in clinic. Further studies will endeavor to identify more combination strategies with Tucidinostat and to identify specific clinical biomarkers to predict the therapeutic effect.
Tucidinostat plus exemestane for postmenopausal patients with advanced, hormone receptor-positive breast cancer (ACE): a randomised, double-blind, placebo-controlled, phase 3 trial
Lancet Oncol 2019 Jun;20(6):806-815.PMID:31036468DOI:10.1016/S1470-2045(19)30164-0.
Background: Tucidinostat (formerly known as chidamide) is an oral subtype-selective histone deacetylase inhibitor. In an exploratory study, the combination of Tucidinostat with exemestane showed preliminary signs of encouraging anti-tumour activity in patients with advanced hormone receptor-positive breast cancer. To build on these findings, we aimed to assess the efficacy and safety of this combination in a randomised trial in a larger population of postmenopausal patients with advanced, hormone receptor-positive breast cancer. Methods: We did the randomised, double-blind, placebo-controlled, phase 3 ACE trial at 22 specialist cancer centres in China. Eligible patients were postmenopausal women (aged ≥60 years or aged <60 years if their serum follicle-stimulating hormone and oestradiol concentrations were within postmenopausal ranges) with hormone receptor-positive, HER2-negative breast cancer, whose disease had relapsed or progressed after at least one endocrine therapy (either in advanced or metastatic or adjuvant setting), and who had at least one measurable lesion, adequate organ function, Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and adequate haematological and biochemical parameters. Endocrine therapy did not have to be the most recent therapy before randomisation, but recurrence or progression after the most recent therapy was a prerequisite. Patients were randomly assigned (2:1) by a dynamic randomisation scheme via an interactive web-response system to receive 30 mg oral Tucidinostat or placebo twice weekly. All patients in both groups also received 25 mg oral exemestane daily. Randomisation was stratified according to the presence of visceral metastases (yes vs no). Patients, investigators, study site staff, and the sponsor were masked to treatment assignment. The primary endpoint was investigator-assessed progression-free survival. Efficacy analyses were done in the full analysis set population, comprising all patients who received at least one dose of any study treatment, and safety analyses were done in all patients who received at least one dose of any study treatment and for whom at least one safety case report form was available. This study is registered with ClinicalTrials.gov, number NCT02482753. The study has reached the required number of events for final analysis of the primary endpoint. The trial is no longer enrolling patients, but follow-up for investigation of overall survival is ongoing. Findings: Between July 20, 2015, and June 26, 2017, 365 patients were enrolled and randomly assigned, 244 to the Tucidinostat group and 121 to the placebo group. The median duration of follow-up was 13·9 months (IQR 9·8-17·5). Investigator-assessed median progression-free survival was 7·4 months (95% CI 5·5-9·2) in the Tucidinostat group and 3·8 months (3·7-5·5) in the placebo group (HR 0·75 [95% CI 0·58-0·98]; p=0·033). The most common grade 3 or 4 adverse events in either group were neutropenia (124 [51%] of 244 patients in the Tucidinostat group vs three [2%] of 121 patients in the placebo group), thrombocytopenia (67 [27%] vs three [2%]), and leucopenia (46 [19%] vs three [2%]). Serious adverse events of any cause occurred in 51 (21%) of 244 patients in the Tucidinostat group and seven (6%) of 121 patients in the placebo group. No treatment-related deaths were reported. Interpretation: Tucidinostat plus exemestane improved progression-free survival compared with placebo plus exemestane in patients with advanced, hormone receptor-positive, HER2-negative breast cancer that progressed after previous endocrine therapy. Grade 3-4 haematological adverse events were more common in the Tucidinostat plus exemestane group than in the placebo plus exemestane group. Tucidinostat plus exemestane could represent a new treatment option for these patients. Funding: Chipscreen Biosciences.
Optimized dose selective HDAC inhibitor Tucidinostat overcomes anti-PD-L1 antibody resistance in experimental solid tumors
BMC Med 2022 Nov 9;20(1):435.PMID:36352411DOI:10.1186/s12916-022-02598-5.
Background: Although immune checkpoint inhibitors (ICIs) have influenced the treatment paradigm for multiple solid tumors, increasing evidence suggests that primary and adaptive resistance may limit the long-term efficacy of ICIs. New therapeutic strategies with other drug combinations are hence warranted to enhance the antitumor efficacy of ICIs. As a novel tumor suppressor, histone deacetylase (HDAC) inhibitor Tucidinostat has been successfully confirmed to act against hematological malignancies. However, the underlying mechanisms of action for Tucidinostat and whether it can manipulate the tumor microenvironment (TME) in solid tumors remain unclear. Methods: Three murine tumor models (4T1, LLC, and CT26) were developed to define the significant role of different doses of Tucidinostat in TME. The immunotherapeutic effect of Tucidinostat combined with anti-programmed cell death ligand 1 antibody (aPD-L1) was demonstrated. Furthermore, the effect of Tucidinostat on phenotypic characteristics of peripheral blood mononuclear cells (PBMCs) from lung cancer patients was investigated. Results: With an optimized dose, Tucidinostat could alter TME and promote the migration and infiltration of CD8+ T cells into tumors, partially by increasing the activity of C-C motif chemokine ligand 5 (CCL5) via NF-κB signaling. Moreover, Tucidinostat significantly promoted M1 polarization of macrophages and increased the in vivo antitumor efficacy of aPD-L1. Tucidinostat also enhanced the expression of the costimulatory molecules on human monocytes, suggesting a novel and improved antigen-presenting function. Conclusions: A combination regimen of Tucidinostat and aPD-L1 may work synergistically to reduce tumor burden in patients with cancer by enhancing the immune function and provided a promising treatment strategy to overcome ICI treatment resistance.
Oral HDAC inhibitor Tucidinostat in patients with relapsed or refractory peripheral T-cell lymphoma: phase IIb results
Haematologica 2023 Mar 1;108(3):811-821.PMID:36200417DOI:10.3324/haematol.2022.280996.
Tucidinostat (formerly known as chidamide) is an orally available, novel benzamide class of histone deacetylase (HDAC) inhibitor that selectively blocks class I and class IIb HDAC. This multicenter phase IIb study aimed to investigate the efficacy and safety of Tucidinostat, 40 mg twice per week (BIW), in patients with relapsed/refractory (R/R) peripheral T-cell lymphoma (PTCL). The primary endpoint was overall response rate (ORR) assessed by an independent overall efficacy review committee. Between March 2017 and March 2019, 55 patients were treated, and 46 and 55 were evaluated for efficacy and safety, respectively. Twenty-one of 46 patients achieved objective responses with an ORR of 46% (95% confidence interval : 30.9-61.0), including five patients with complete response (CR). Responses were observed across various PTCL subtypes. In angioimmunoblastic T-cell lymphoma, there were two CR and five partial responses (PR) among eight patients, achieving an ORR of 88%. The disease control rate (CR + PR + stable disease) was 72% (33/46). The median progression-free survival, duration of response, and overall survival were 5.6 months, 11.5 months, 22.8 months, respectively. The most common adverse events (AE) (all grades) were thrombocytopenia, neutropenia, leukopenia, anemia, and diarrhea. The grade ≥3 AE emerging in ≥20% of patients included thrombocytopenia (51%), neutropenia (36%), lymphopenia (22%), and leukopenia (20%). Importantly, most of the AE were manageable by supportive care and dose modification. In conclusion, the favorable efficacy and safety profiles indicate that Tucidinostat could be a new therapeutic option in patients with R/R PTCL (clinicaltrials gov. Identifier: NCT02953652).