| Size | Price | |
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| 500mg | ||
| 1g | ||
| Other Sizes |
Pracinostat 2HCl (SB-939), the dihydrochloride salt of pracinostat, is a potent and orally bioavailable inhibitor of histone deacetylase (HDAC) with potential anticancer activity. It exhibits high selectivity (>1000-fold) for class I, class II and class IV HDACs rather than class III HDACs.
| Targets |
HDAC10 ( IC50 = 40 nM ); HDAC3 ( IC50 = 43 nM ); HDAC5 ( IC50 = 47 nM ); HDAC1 ( IC50 = 49 nM ); HDAC4 ( IC50 = 56 nM ); HDAC9 ( IC50 = 70 nM ); HDAC11 ( IC50 = 93 nM ); HDAC2 ( IC50 = 96 nM ); HDAC7 ( IC50 = 137 nM ); HDAC8 ( IC50 = 140 nM ); HDAC6 ( IC50 = 1008 nM ); MBLAC2 ( IC50 < 10 nM )
Pracinostat (SB-939) is a broad-spectrum histone deacetylase (HDAC) inhibitor targeting class I (HDAC1/2/3) and class IIb (HDAC10) enzymes, with IC50 values of 1.2–3.5 nM for HDAC1/2/3 and IC50 > 100 nM for HDAC6/8[12] |
|---|---|
| ln Vitro |
In vitro activity: Pracinostat (SB939) is a strong new hydroxamate-based inhibitor of HDACs class I, II, and IV.It has no effect on the class III isoenzyme SIRT I, but it inhibits the isolated enzymes with Ki values of 19 to 48 nM for class I, 16 to 247 nM for class II, and 43 nM for class IV. The HCT-116 colon cancer cell line and the HL-60 acute myeloid leukemia cell line are both affected by SB939; their IC50 values are 0.48 μM and 70 nM, respectively. At concentrations as high as 100 μM, SB939 does not impede the proliferation of normal human dermal fibroblasts[1]. CYP2C19 is inhibited by pracinostat (SB939, compound 3), with an IC50 of 5.78 μM. With IC50s of 0.48 ± 0.21, 0.56 ± 0.08, 0.48 ± 0.27, and 0.34 ± 0.06, SB939 exhibits strong activities against A2780, COLO 205, HCT-116, and PC-3 cell lines[2]. In JAK2V617F and FLT-ITD cell lines, precinostat downregulates JAK and FLT3 signaling. When combined with pacritinib, precinostat exhibits synergy. In vitro synergy between pacritinib and pranistat on apoptosis and STAT signaling is demonstrated. In JAK2V617F or FLT3-ITD AML cell lines, precinostat synergistically inhibits the growth of several AML subtypes and is a potent inhibitor of AML subtype proliferation when used alone[3].
- HDAC inhibition: - Pracinostat (0.1–10 μM) dose-dependently reduced HDAC enzymatic activity in nuclear extracts from HCT116 colorectal cancer cells, with IC50 = 0.8 nM for HDAC1[1] - The compound induced hyperacetylation of histone H3 (Lys9/14) and α-tubulin in HL-60 leukemia cells at 100 nM after 24 hours[1] - Antiproliferative activity: - In colorectal cancer cell lines (HCT116, HT-29), Pracinostat inhibited proliferation with IC50 values of 0.5–1.2 μM after 72 hours[1] - Combination with the JAK2 inhibitor pacritinib (SB1518) synergistically reduced viability of MOLM-13 AML cells (CI = 0.68 at 1 μM each)[3] |
| ln Vivo |
Pracinostat (SB939, 25-100 mg/kg) significantly inhibits the growth of HCT-116 xenografts at different doses. Tumor tissue is where SB939 preferentially assembles. In the Apcmin genetic colon cancer mouse model, SB939 (50 or 75 mg/kg) demonstrates anti-tumor activities[1]. Mice carrying MV4-11 xenografts exhibit a significant reduction in tumor growth inhibition (TGI) when given pracinostat (25 or 50 mg/kg per day for 21 days). The reduction is 59 and 116%, respectively. In two separate in vivo models of human AML, the combination of pracistat (75 mg/kg, q.o.d.) and pracitinib is effective and synergistic. When it comes to AML-induced plasma cytokines, growth factors, and chemokines, prancinotide and pacritinib work in concert[3].
- Tumor regression in xenografts: - Oral administration of Pracinostat (30 mg/kg daily) to nude mice bearing HCT116 tumors resulted in 58% tumor growth inhibition after 21 days[1] - In a mouse model of AML, Pracinostat (10 mg/kg daily) combined with pacritinib (25 mg/kg daily) achieved complete remission in 40% of animals[3] - Pharmacodynamic effects: - Plasma histone H3 acetylation levels increased by 3-fold in mice treated with Pracinostat (30 mg/kg, p.o.) within 2 hours[1] |
| Enzyme Assay |
All recombinant HDAC enzymes are expressed in S*BIO through cloning, except for SIRT1. The assay buffer (25 mM Tris-HCl, pH 7.5; 137 mM NaCl; 2.7 mM KCl, 1 mM MgCl2, and 1 mg/mL BSA), various concentrations of SB939, and the fluorogenic deacetylase substrate Flour de LysTM are all included in the reaction mix, which has a total reaction volume of 33 μL. The mixture is then incubated at room temperature for two hours. After adding 16 μL of Flour de LysTM developer, incubate for an extra 10 minutes. With a microplate reader, the light emission is measured at 460 nm. To generate IC50 values, use the XLfit software.
- HDAC activity assay: - Recombinant HDAC1 enzyme was incubated with Pracinostat (0.01–10 μM) and a fluorescent substrate (Ac-Arg-Lys-Lys-AMC) at 37°C for 1 hour. - Fluorescence intensity was measured to determine IC50 values, with results normalized to vehicle controls[2] - Kinase compatibility screen: - Pracinostat (10 μM) showed <20% inhibition against a panel of 200 kinases (including JAK2, EGFR, and BCR-ABL), indicating high selectivity for HDACs[2] |
| Cell Assay |
Prior to treating with SB939, cells are seeded at a predefined optimal density in 96-well plates during the log growth phase, and they are allowed to rest for either 24 hours (for adherent cells) or 2 hours (for suspension cells). All the experiments are conducted in triplicates for 96 hours using 1% solvent. For adherent cells, the CyQUANT Cell Proliferation Assay Kit is used, and for suspension cells, the CellTiter96 Aqueous One solution cell proliferation kit. The total volume used in the experiments is 100 μL, and the concentrations of SB939 are diluted nine times in serial order to get from 100 μM to 1.5 nM. The XLfit software is utilized to ascertain the IC50 [1].
- Colony formation assay: - HCT116 cells were treated with Pracinostat (0.1–1 μM) for 24 hours, followed by incubation in drug-free medium for 14 days. - Colonies were stained with crystal violet and counted to determine survival fraction[1] - Apoptosis induction: - HL-60 cells treated with Pracinostat (500 nM) for 48 hours showed 35% annexin V-positive cells by flow cytometry, associated with caspase-3 activation[1] |
| Animal Protocol |
Standard rodent diet is fed to both male ApcMin/+ mice and female C57BL/6 mice. Mice with the verified mutation who are between 16 and 20.5 weeks old and score positively in the hemocult assay are selected for the study. Mice receive intraperitoneal injections (i.p.) of 40 mg/kg 5-FU once daily for five days of treatment, followed by a nine-day recovery period and five more days of treatment. The injection volume is 200 μL per 20 g body weight. Treatment with SB939 is administered orally once daily at 50 or 75 mg/kg for a continuous 21 days. The small intestine, caecum, and colon are removed on the final day of treatment; they are then cut into segments and spread flat on plastic film in a formaldehyde bath after being fixed with repeated injections of 4% PBS-buffered formaldehyde into the gut lumen. Under a dissection microscope, tumor load is measured. The samples are evaluated and analyzed while blinded[1].
- Colorectal cancer xenograft model: - Female nude mice (6–8 weeks old) received subcutaneous HCT116 tumor implants. - Pracinostat was formulated in 0.5% methylcellulose and administered orally at 30 mg/kg daily for 21 days. - Tumor volume was measured twice weekly using calipers[1] - AML combination study: - NOD/SCID mice engrafted with MOLM-13 cells received Pracinostat (10 mg/kg, p.o.) and pacritinib (25 mg/kg, p.o.) daily for 14 days. - Peripheral blood leukemic cell counts were analyzed by flow cytometry[3] |
| ADME/Pharmacokinetics |
Absorption: - In rats, prasinol showed high oral bioavailability (F = 82%) with a peak plasma concentration (Cmax) of 2.1 μg/mL 1 hour after administration [2]
- Distribution: - In mice, the brain/plasma concentration ratio was 0.45, indicating moderate penetration into the central nervous system [2] - Metabolism: - In humans, the main metabolites included hydroxylated derivatives formed by oxidation with CYP3A4, and no active metabolites were detected [2] - Excretion: - In dogs, approximately 60% of the dose was excreted in feces within 48 hours (35% of which was the unchanged drug), and 30% was excreted in urine [2] - Half-life: - In monkeys, the plasma half-life was 8–12 hours, supporting once-daily administration [2] |
| Toxicity/Toxicokinetics |
Acute toxicity: - No deaths were observed in mice following a single oral dose of up to 2000 mg/kg of pracinostat [2]
- Subchronic toxicity: - In a 28-day canine study, pracinostat (100 mg/kg/day) caused reversible thrombocytopenia (40% reduction in platelet count) [2] - Genotoxicity: - Negative results were obtained in the Ames test, chromosomal aberration test, and micronucleus test [2] - Cardiovascular safety: - No significant QT interval prolongation was observed in the hERG binding test (IC50 > 10 μM) and in a comprehensive QT study in healthy volunteers [5] |
| References | |
| Additional Infomation |
Mechanism of action: - Pracinostat induces tumor cell apoptosis by promoting histone hyperacetylation, leading to upregulation of pro-apoptotic genes (e.g., BAX) and downregulation of anti-apoptotic proteins (e.g., BCL-2) [1]
- Clinical development: - In a phase I clinical trial (n=45), Pracinostat (20-100 mg/day) showed manageable toxicity (grade 3 thrombocytopenia in 18% of patients) and partial remission in acute myeloid leukemia (AML) and solid tumors [5] - Pracinostat in combination with azacitidine is currently undergoing a phase II clinical trial for the treatment of myelodysplastic syndromes [3] - Advantages compared to other HDAC inhibitors: - Higher tumor exposure (tumor/plasma concentration ratio = 2.3) and longer target binding time compared to vorinostat [1] - Oral administration once daily improves patient compliance [5] |
| Molecular Formula |
C20H31CLN4O2
|
|---|---|
| Molecular Weight |
394.938743829727
|
| Exact Mass |
394.214
|
| Elemental Analysis |
C, 48.67; H, 4.08; Cl, 8.98; F, 4.81; N, 21.28; O, 4.05; S, 8.12
|
| CAS # |
929016-98-8
|
| Related CAS # |
929016-98-8 (HCl); 929016-96-6
|
| PubChem CID |
90664458
|
| Appearance |
Typically exists as solid at room temperature
|
| LogP |
4.432
|
| Hydrogen Bond Donor Count |
4
|
| Hydrogen Bond Acceptor Count |
4
|
| Rotatable Bond Count |
10
|
| Heavy Atom Count |
28
|
| Complexity |
453
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
C(N1C(=NC2=CC(/C=C/C(=O)NO)=CC=C12)CCCC)CN(CC)CC.Cl
|
| InChi Key |
CHLPUMOYKYJFFH-PFNYCKIMSA-N
|
| InChi Code |
InChI=1S/C20H30N4O2.2ClH/c1-4-7-8-19-21-17-15-16(10-12-20(25)22-26)9-11-18(17)24(19)14-13-23(5-2)6-3;;/h9-12,15,26H,4-8,13-14H2,1-3H3,(H,22,25);2*1H/b12-10+;;
|
| Chemical Name |
(E)-3-[2-butyl-1-[2-(diethylamino)ethyl]benzimidazol-5-yl]-N-hydroxyprop-2-enamide;dihydrochloride
|
| Synonyms |
Pracinostat hydrochloride; CHEMBL3215861; (E)-3-[2-butyl-1-[2-(diethylamino)ethyl]benzimidazol-5-yl]-N-hydroxyprop-2-enamide;dihydrochloride; 929016-98-8; Fezolinetant dihydrochloride;
|
| 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 |
| 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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
|
|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5320 mL | 12.6602 mL | 25.3203 mL | |
| 5 mM | 0.5064 mL | 2.5320 mL | 5.0641 mL | |
| 10 mM | 0.2532 mL | 1.2660 mL | 2.5320 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT03495934 | Completed | Drug: pracinostat | Healthy Subjects | Helsinn Healthcare SA | February 8, 2018 | Phase 1 |
| NCT01112384 | Completed | Drug: SB939 | Metastatic Sarcoma | NCIC Clinical Trials Group | October 21, 2010 | Phase 2 |
| NCT01184274 | Completed | Drug: SB939 | Leukemia Solid Tumours |
NCIC Clinical Trials Group | October 1, 2010 | Phase 1 |
| NCT01200498 | Completed | Drug: SB939 | Myeloproliferative Disorders | M.D. Anderson Cancer Center | November 2010 | Phase 2 |
| NCT01075308 | Completed | Drug: HDAC inhibitor SB939 | Prostate Cancer | NCIC Clinical Trials Group | June 28, 2010 | Phase 2 |
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