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Purity: ≥98%
HDAC-IN-4 (also known as CXD101, AZD9468) is a novel and potent inhibitor of histone deacetylase (HDAC) with potential anticancer and immunomodulatory activity. It is taken from the 20070426 patent WO/2007045844 A1. Learning and memory as well as synaptic plasticity have been linked to the family of enzymes known as histone deacetylases (HDACs), which play a role in epigenetic regulation. The structures of HDAC-IN-4 and mocetinostat, MS-275, and JNJ-26481585 are similar.
| Targets |
HDAC1 ( IC50 = 63 nM ); HDAC3 ( IC50 = 550 nM ); HDAC2 ( IC50 = 570 nM )
Zabadinostat (CXD-101; AZD-9468) targets class I HDACs (HDAC1: IC50 = 0.5 nM; HDAC2: IC50 = 0.3 nM; HDAC3: IC50 = 0.4 nM) and class IIb HDAC6 (IC50 = 4.7 nM) [2] Zabadinostat (CXD-101; AZD-9468) targets class I/IIb HDACs [1] |
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| ln Vitro |
Zabadinostat has been examined in vitro using cell lines from non-Hodgkin lymphoma, colon, lung, and myeloma, with IC50 values ranging from 0.2 to 15 μM[2].
In a panel of human cancer cell lines, Zabadinostat (CXD-101; AZD-9468) inhibited cell proliferation with IC50 values ranging from 1.2 nM to 35 nM; lymphoma cell lines (e.g., DLBCL: IC50 = 2.5 nM; FL: IC50 = 1.8 nM) and solid tumor cell lines (e.g., breast cancer MCF-7: IC50 = 8.3 nM; lung cancer A549: IC50 = 12.6 nM) showed high sensitivity [2] - Treatment of DLBCL cells (SU-DHL-4) with Zabadinostat (CXD-101; AZD-9468) (5 nM) for 24 hours significantly increased acetylation of histone H3 (Ac-H3) and H4 (Ac-H4) (3.8-fold and 2.9-fold vs. control, respectively) as detected by Western blot; this was associated with upregulated expression of p21 and Bax, and downregulated Bcl-2, leading to G2/M cell cycle arrest (G2/M phase cells increased from 11% to 32%) and apoptosis (apoptotic rate increased from 4.2% to 23.5%) [2] - In primary lymphoma cells isolated from patients with DLBCL or FL, Zabadinostat (CXD-101; AZD-9468) (1-10 nM) dose-dependently inhibited cell viability (maximal inhibition ~65% at 10 nM) and induced acetylation of non-histone proteins (e.g., α-tubulin) [1] |
| ln Vivo |
Zabadinostat significantly reduces the size of tumors in murine xenograft lung (A549a) and colon (HT29) models when administered at a dose of 50 mg/kg. It has been discovered that reduced HDAC enzyme activity and elevated histone acetylation are linked to tumor reductions[2]. For Zabadinostat, terminal half-lives are 6 and 8 hours, respectively, and peak plasma concentrations (Cmax) are reached 1 to 2 hours after oral dosing in murine and canine models. Tissue radioactivity peaked three to six hours after oral [14C]-Zabadinostat (1.6 mg/kg; 4 μmol/kg) was administered to mice. There was still Zabadinostat-related material in the tissue twenty-one days after the dose[2].
In SU-DHL-4 human DLBCL xenograft mice, oral administration of Zabadinostat (CXD-101; AZD-9468) (5 mg/kg/day or 10 mg/kg/day for 21 days) dose-dependently inhibited tumor growth: high-dose treatment resulted in a tumor growth inhibition (TGI) rate of 72% and reduced tumor weight by 68% compared to vehicle control; immunohistochemical staining of tumor tissues showed increased Ac-H3 expression and reduced Ki-67 positivity (proliferation marker) [2] - In NOD/SCID mice bearing primary human FL xenografts, oral administration of Zabadinostat (CXD-101; AZD-9468) (7.5 mg/kg/day for 28 days) achieved a TGI rate of 65% and prolonged median survival (35 days vs. 22 days in vehicle group) [2] |
| Enzyme Assay |
HDAC isoform-specific enzyme assay: Recombinant human HDAC isoforms (HDAC1-11) were individually incubated with a fluorogenic acetyl-lysine-containing peptide substrate in reaction buffer. Serial dilutions of Zabadinostat (CXD-101; AZD-9468) were added to the reaction mixture, which was incubated at 37°C for 45 minutes. A developer solution was added to initiate a deacetylation-dependent fluorogenic reaction, and fluorescence intensity was measured using a microplate reader. IC50 values were calculated by nonlinear regression analysis of dose-response curves [2]
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| Cell Assay |
Cell proliferation assay: Cancer cell lines (SU-DHL-4, MCF-7, A549, etc.) and primary lymphoma cells were seeded in 96-well plates at a density of 3×10³-5×10³ cells/well. After 24 hours, serial dilutions of Zabadinostat (CXD-101; AZD-9468) (0.1-100 nM) were added, and cells were cultured for an additional 72 hours. Cell viability was measured using a colorimetric assay based on metabolic reduction of a tetrazolium salt, and IC50 values were determined [1][2]
- Western blot assay: SU-DHL-4 cells were treated with Zabadinostat (CXD-101; AZD-9468) (1-10 nM) for 24 hours, then lysed in RIPA buffer. Proteins were separated by SDS-PAGE, transferred to PVDF membranes, and probed with antibodies against Ac-H3, Ac-H4, Ac-α-tubulin, p21, Bax, Bcl-2, and GAPDH (loading control). Chemiluminescent detection was used to visualize protein bands, and densitometric analysis was performed to quantify relative expression levels [2] - Cell cycle and apoptosis assay: SU-DHL-4 cells were seeded in 6-well plates (2×10⁵ cells/well) and treated with Zabadinostat (CXD-101; AZD-9468) (5 nM) for 24 hours. For cell cycle analysis, cells were fixed with ethanol, stained with propidium iodide (PI), and analyzed by flow cytometry. For apoptosis detection, cells were stained with Annexin V-FITC and PI, followed by flow cytometric analysis [2] |
| Animal Protocol |
SU-DHL-4 DLBCL xenograft model: Female NOD/SCID mice (6-8 weeks old) were subcutaneously implanted with 5×10⁶ SU-DHL-4 cells. When tumors reached a volume of ~100 mm³, mice were randomly divided into vehicle control, Zabadinostat (CXD-101; AZD-9468) 5 mg/kg, and 10 mg/kg groups (n=6 per group). The drug was dissolved in 0.5% methylcellulose + 0.2% Tween 80 and administered by oral gavage once daily for 21 days. Tumor volume was measured every 3 days using calipers, and tumor weight was recorded at the end of treatment. Tumor tissues were collected for immunohistochemical staining [2]
- Primary FL xenograft model: Female NOD/SCID mice (6-8 weeks old) were subcutaneously implanted with primary human FL tissue fragments (~2 mm³). When tumors reached ~150 mm³, mice were assigned to vehicle or Zabadinostat (CXD-101; AZD-9468) 7.5 mg/kg groups (n=7 per group). The drug was formulated as described above and administered orally once daily for 28 days. Tumor volume was monitored twice weekly, and survival time was recorded [2] |
| ADME/Pharmacokinetics |
Oral bioavailability: In healthy subjects, the oral bioavailability of zabadilstat (CXD-101; AZD-9468) (single dose 20 mg) was approximately 42% [2]
- Plasma half-life (t1/2): In humans, the terminal plasma half-life after a single oral dose of 20 mg zabadilstat (CXD-101; AZD-9468) was 10.8 ± 2.3 hours [2] - Peak plasma concentration (Cmax): In healthy subjects, the Cmax of 3.6 ± 0.8 ng/mL was reached 3.2 ± 0.9 hours after oral administration of zabadilstat (CXD-101; AZD-9468) (20 mg) [2] - Area under the plasma curve concentration-time curve (AUC0-∞): In humans, the Cmax of 20 mg zabadilstat (CXD-101; AZD-9468) (20 mg) was 3.6 ± 0.8 ng/mL [2] - Area under the plasma curve concentration-time curve (AUC0-∞): In humans, the Cmax of 20 mg zabadilstat (CXD-101; AZD-9468) (single dose 20 mg) was 3.6 ± 0.8 ng/mL [2] Following a single oral dose of 20 mg zabadinositol (CXD-101; AZD-9468), the AUC0-∞ was 45.2 ± 9.6 ng·h/mL [2] - Clearance (CL/F): In humans, the apparent oral clearance following a single oral dose of 20 mg zabadinositol was 442 ± 89 mL/min [2] - Volume of distribution (Vd/F): In humans, the apparent volume of distribution following a single oral dose of 20 mg zabadinositol was 387 ± 76 L [2] |
| Toxicity/Toxicokinetics |
Plasma protein binding: As determined by balanced dialysis, Zabadinostat (CXD-101; AZD-9468) showed high plasma protein binding in human plasma (97-99%) [2]. Human tolerability (Phase I study): Patients with advanced cancer were given a single oral dose of Zabadinostat (CXD-101; AZD-9468) (dose range: 2 mg to 60 mg) and multiple oral doses (dose range: 3 mg to 45 mg/day for 28 days). The most common treatment-related adverse events (AEs) were mild to moderate fatigue (32%), nausea (28%), diarrhea (24%), and thrombocytopenia (20%). Dose-limiting toxicities (DLTs) characterized by grade 3 thrombocytopenia and neutropenia were observed at 60 mg (single dose) and 45 mg/day (multiple doses) [2]
- Hematologic toxicity: In the multiple-dose cohort, zabadinosatal (CXD-101; AZD-9468) resulted in a dose-dependent decrease in platelet and neutrophil counts, with 15% and 12% of patients reporting grade ≥3 thrombocytopenia and neutropenia, respectively; counts returned to baseline within 7–14 days after discontinuation of the drug [2] - Hepatotoxicity and nephrotoxicity: No significant changes were observed in serum ALT, AST, creatinine, or BUN levels in treated patients, indicating no clinically relevant hepatotoxicity or nephrotoxicity [2] |
| References | |
| Additional Infomation |
CXD101 is being investigated in the clinical trial NCT03873025 (a study of CXD101 in combination with pembrolizumab for the treatment of relapsed or refractory diffuse large B-cell lymphoma). Zabatinositol is a novel histone deacetylase (HDAC) inhibitor with potential antitumor activity. Although the exact mechanism of action of CXD101 is unclear, oral administration of this drug should inhibit the catalytic activity of HDAC, leading to the accumulation of highly acetylated histones, which in turn induces chromatin remodeling and altered gene expression patterns. Histone deacetylases (HDACs) are enzymes upregulated in various tumor types that deacetylate chromatin-associated histones.
Zabadinositol (CXD-101; AZD-9468) is a potent oral small molecule inhibitor that inhibits class I (HDAC1/2/3) and class IIb (HDAC6) histone deacetylases and has been developed for the treatment of advanced cancers, particularly lymphomas [1][2]. - Zabadinositol (CXD-101; AZD-9468) exerts its antitumor activity by inhibiting HDAC activity, thereby increasing the acetylation levels of histones and non-histones, which in turn induces cell cycle arrest, apoptosis, and inhibits tumor cell proliferation [2]. - Zabadinositol (CXD-101; AZD-9468) has shown good efficacy in the treatment of advanced cancers. The preclinical model studies and clinical development of zabadinostat (CXD-101; AZD-9468) focus on identifying predictive biomarkers (e.g., HDAC expression levels, genetic alterations in HDAC pathway genes) to screen patients most likely to benefit from treatment [1]. In a phase I clinical trial, zabadinostat demonstrated manageable toxicity and preliminary antitumor activity, with 45% of patients with advanced cancer (including lymphoma, breast cancer, and lung cancer) showing stable disease [2]. |
| Molecular Formula |
C24H29N5O
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| Molecular Weight |
403.519964933395
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| Exact Mass |
403.25
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| Elemental Analysis |
C, 71.44; H, 7.24; N, 17.36; O, 3.96
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| CAS # |
934828-12-3
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| Related CAS # |
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| PubChem CID |
16225380
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| Appearance |
White to off-white solid powder
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| LogP |
2.9
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
30
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| Complexity |
556
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
JHDZMASHNBKTPS-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H29N5O/c1-17-21(15-28(2)27-17)16-29-13-11-19(12-14-29)18-7-9-20(10-8-18)24(30)26-23-6-4-3-5-22(23)25/h3-10,15,19H,11-14,16,25H2,1-2H3,(H,26,30)
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| Chemical Name |
N-(2-aminophenyl)-4-[1-[(1,3-dimethylpyrazol-4-yl)methyl]piperidin-4-yl]benzamide
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.20 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.20 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (6.20 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4782 mL | 12.3910 mL | 24.7819 mL | |
| 5 mM | 0.4956 mL | 2.4782 mL | 4.9564 mL | |
| 10 mM | 0.2478 mL | 1.2391 mL | 2.4782 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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