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Pracinostat (SB939)

Pan-HDAC inhibitor CAS# 929016-96-6

Pracinostat (SB939)

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Chemical structure

Pracinostat (SB939)

3D structure

Chemical Properties of Pracinostat (SB939)

Cas No. 929016-96-6 SDF Download SDF
PubChem ID 49855250 Appearance Powder
Formula C20H30N4O2 M.Wt 358.48
Type of Compound N/A Storage Desiccate at -20°C
Synonyms SB939
Solubility DMSO : 50 mg/mL (139.48 mM; Need ultrasonic)
Chemical Name (E)-3-[2-butyl-1-[2-(diethylamino)ethyl]benzimidazol-5-yl]-N-hydroxyprop-2-enamide
SMILES CCCCC1=NC2=C(N1CCN(CC)CC)C=CC(=C2)C=CC(=O)NO
Standard InChIKey JHDKZFFAIZKUCU-ZRDIBKRKSA-N
Standard InChI InChI=1S/C20H30N4O2/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)/b12-10+
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of Pracinostat (SB939)

DescriptionPracinostat (SB939) is a potent inhibitor of HDAC with IC50 of 40-140 nM with exception for HDAC6.
TargetsHDAC1HDAC3HDAC4HDAC5HDAC9HDAC10
IC5049 nM43 nM56 nM47 nM70 nM40 nM

Protocol

Cell experiment:

Cell lines

Ovarian (A2780) , colon (HCT-116), and prostate (PC-3) cell lines

Preparation method

The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months.

Reacting condition

96 h; IC50=0.48±0.21 μM (A2780), 0.48±0.27 μM (HCT-116), 0.34±0.06 μM (PC-3)

Applications

SB939 showed broad anti-proliferative activity against representative tumor cells from ovarian (A2780) , colon (HCT-116), and prostate (PC-3) with cellular IC50 values of 0.48±0.21, 0.48±0.27 and 0.34±0.06 μM, respectively.

Animal experiment:

Animal models

Athymic nude mice

Dosage form

200 mg/kg, 100 mg/kg, 50 mg/kg; oral taken.

Application

SB939 was clearly toxic at the highest dose tested (200 mg/kg); however, at the MTD dose of 100 mg/kg and at 50mg/kg, it demonstrated very significant antitumor effects on day 21 with TGI = 90% (p < 0.001 ) and 66% ( p < 0.001), respectively, with acceptable body weight loss.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

References:

[1] Wang H, Yu N, Chen D, et al. Discovery of (2 E)-3-{2-butyl-1-[2-(diethylamino) ethyl]-1 H-benzimidazol-5-yl}-N-hydroxyacrylamide (SB939), an orally active histone deacetylase inhibitor with a superior preclinical profile[J]. Journal of medicinal chemistry, 2011, 54(13): 4694-4720.

Pracinostat (SB939) Dilution Calculator

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Preparing Stock Solutions of Pracinostat (SB939)

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.7896 mL 13.9478 mL 27.8956 mL 55.7911 mL 69.7389 mL
5 mM 0.5579 mL 2.7896 mL 5.5791 mL 11.1582 mL 13.9478 mL
10 mM 0.279 mL 1.3948 mL 2.7896 mL 5.5791 mL 6.9739 mL
50 mM 0.0558 mL 0.279 mL 0.5579 mL 1.1158 mL 1.3948 mL
100 mM 0.0279 mL 0.1395 mL 0.279 mL 0.5579 mL 0.6974 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

Research Update of Pracinostat (SB939)

1. Antimalarial activity of the anticancer histone deacetylase inhibitor SB939. Antimicrob Agents Chemother. 2012 Jul;56(7):3849-56. doi: 10.1128/AAC.00030-12. Epub 2012 Apr 16.
Abstract
SB939 is a HDAC that potently inhibited the growth of multiple malarial parasites at different life stages.
2. Preclinical metabolism and disposition of SB939 (Pracinostat), an orally active histone deacetylase inhibitor, and prediction of human pharmacokinetics. Drug Metab Dispos. 2011 Dec;39(12):2219-32. doi: 10.1124/dmd.111.041558. Epub 2011 Aug 26.
Abstract
The preclinical ADME properties of SB939, a orally active HDAC inhibitor primarily metabolized by CYP3A4 and CYP1A2 in human, have been characterized in human and animals, where observed ADME of SB939 in human were consistent with predication s by Simcyp and allometric scaling.
4. A phase I study of histone deacetylase inhibitor, pracinostat (SB939), in pediatric patients with refractory solid tumors: IND203 a trial of the NCIC IND program/C17 pediatric phase I consortium. Pediatr Blood Cancer. 2013 Nov;60(11):1868-74. doi: 10.1002/pbc.24694. Epub 2013 Jul 25.
Abstract
With a RP2D of 60 mg po t.i.w. for 3 weeks every 4 weeks in adult patients, the toxicities, PKs and RP2D of SB939, an inhibitor of class 1/2/4 HDAC, have been investigated in children with refractory solid tumors.
5. Pharmacodynamic evaluation of the target efficacy of SB939, an oral HDAC inhibitor with selectivity for tumor tissue. Mol Cancer Ther. 2011 Jul;10(7):1207-17. doi: 10.1158/1535-7163.MCT-11-0044. Epub 2011 May 17.
Abstract
SB939, an inhibitor of class 1/2/4 HDACs, exhibited favorable PKs and PDs in preclinical models leading to successful applications to patients, where SB939 dose- and time-dependently induced acH3 accumulation in cancerous tissues and leukemic bone marrow.

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Background on Pracinostat (SB939)

Pracinostat, also known as SB939, is a potent and orally available inhibitor of histone deacetylase (HDAC) with a relatively stronger selectivity (more than 1000-fold) for class I, class II and class IV HDACs rather than class III HDACs. Pracinostat potently suppresses proliferation in a wide range of cancer cell lines, including colon cancer, ovarian cancer, prostate carcinomas, acute myeloid leukaemia (AML) and B cell lymphoma. Recent study results have shown that SB939 induces the accumulation of acetylated histone H3 (AcH3) and acetylated α-tubulin and increases the expression of the cyclin dependent kinase inhibitor p21 in cancer cells.

Reference

Razak AR, Hotte SJ, Siu LL, Chen EX, Hirte HW, Powers J, Walsh W, Stayner LA, Laughlin A, Novotny-Diermayr V, Zhu J, Eisenhauer EA. Phase I clinical, pharmacokinetic and pharmacodynamic study of SB939, an oral histone deacetylase (HDAC) inhibitor, in patients with advanced solid tumours. Br J Cancer. 2011;104(5):756-762.

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References on Pracinostat (SB939)

A phase I study of histone deacetylase inhibitor, pracinostat (SB939), in pediatric patients with refractory solid tumors: IND203 a trial of the NCIC IND program/C17 pediatric phase I consortium.[Pubmed:23893953]

Pediatr Blood Cancer. 2013 Nov;60(11):1868-74.

BACKGROUND: Pracinostat (SB939) is a potent oral inhibitor of class 1, 2, and 4 histone deacetylases (HDAC). The adult recommended phase II dose (RP2D) is 60 mg po three times per week (t.i.w.) for 3 weeks every 4 weeks. This study assessed the toxicities and pharmacokinetics of pracinostat and determined the RP2D in children with refractory solid tumors. METHODS: Pediatric patients with refractory solid tumors were treated with oral pracinostat t.i.w. for 3 consecutive weeks, followed by 1 week off dosing. Three dose levels-25, 35, and 45 mg/m(2) were evaluated using a standard 3 + 3 cohort design. Pharmacokinetic (PK) studies were optional. RESULTS: Twelve patients were enrolled. The most common diagnosis was Ewing sarcoma. Most adverse events (AEs) were hematological with five (40%) patients experiencing grade 3 neutropenia. Non-hematological AEs were generally grade 1. No dose limiting toxicities occurred. More hematological and non-hematological AEs occurred at 45 mg/m(2) : Two of five patients experienced Grade 3 neutropenia and one each Grade 3 thrombocytopenia and leucopenia, Grade 1 fatigue and anorexia occurred in three. The RP2D was declared to be 45 mg/m(2) (comparable to an adult dose of 80 mg). One patient had a best response of stable disease (duration of 2.9 months). Three patients on 25 mg/m(2) and one each on 35 and 45 mg/m(2) participated in the PK study. No dose related changes in Cmax or AUC occurred. CONCLUSIONS: Pracinostat is reasonably well tolerated in children with refractory solid tumors. The RP2D is 45 mg/m(2) .

Preclinical metabolism and disposition of SB939 (Pracinostat), an orally active histone deacetylase inhibitor, and prediction of human pharmacokinetics.[Pubmed:21873472]

Drug Metab Dispos. 2011 Dec;39(12):2219-32.

The preclinical absorption, distribution, metabolism, and excretion (ADME) properties of Pracinostat [(2E)-3-[2-butyl-1-[2-(diethylamino) ethyl]-1H-benzimidazol-5-yl]-N-hydroxyarylamide hydrochloride; SB939], an orally active histone deacetylase inhibitor, were characterized and its human pharmacokinetics (PK) was predicted using Simcyp and allometric scaling. SB939 showed high aqueous solubility with high Caco-2 permeability. Metabolic stability was relatively higher in dog and human liver microsomes than in mouse and rat. The major metabolites formed in human liver microsomes were also observed in preclinical species. Human cytochrome P450 (P450) phenotyping showed that SB939 was primarily metabolized by CYP3A4 and CYP1A2. SB939 did not significantly inhibit human CYP3A4, 1A2, 2D6, and 2C9 (>25 muM) but inhibited 2C19 (IC(50) = 5.8 muM). No significant induction of human CYP3A4 and 1A2 was observed in hepatocytes. Plasma protein binding in mouse, rat, dog, and human ranged between approximately 84 and 94%. The blood-to-plasma ratio was approximately 1.0 in human blood. SB939 showed high systemic clearance (relative to liver blood flow) of 9.2, 4.5, and 1.5 l . h(-1) . kg(-1) and high volume of distribution at steady state (>0.6 l/kg) of 3.5, 1.7, and 4.2 l/kg in mouse, rat, and dog, respectively. The oral bioavailability was 34, 65, and approximately 3% in mice, dogs, and rats, respectively. The predicted oral PK profile and parameters of SB939, using Simcyp and allometric scaling, were in good agreement with observed data in humans. Simcyp predictions showed lack of CYP3A4 and 2C19 drug-drug interaction potential for SB939. In summary, the preclinical ADME of SB939 supported its preclinical and clinical development as an oral drug candidate.

The oral HDAC inhibitor pracinostat (SB939) is efficacious and synergistic with the JAK2 inhibitor pacritinib (SB1518) in preclinical models of AML.[Pubmed:22829971]

Blood Cancer J. 2012 May;2(5):e69.

Acute myeloid leukemia (AML) is currently treated with aggressive chemotherapy that is not well tolerated in many elderly patients, hence the unmet medical need for effective therapies with less toxicity and better tolerability. Inhibitors of FMS-like tyrosine kinase 3 (FLT3), JAK2 and histone deacetylase inhibitors (HDACi) have been tested in clinical studies, but showed only moderate single-agent activity. High efficacy of the HDACi pracinostat treating AML and synergy with the JAK2/FLT3 inhibitor pacritinib is demonstrated. Both compounds inhibit JAK-signal transducer and activator of transcription (STAT) signaling in AML cells with JAK2(V617F) mutations, but also diminish FLT3 signaling, particularly in FLT3-ITD (internal tandem duplication) cell lines. In vitro, this combination led to decreased cell proliferation and increased apoptosis. The synergy translated in vivo in two different AML models, the SET-2 megakaryoblastic AML mouse model carrying a JAK2(V617F) mutation, and the MOLM-13 model of FLT3-ITD-driven AML. Pracinostat and pacritinib in combination showed synergy on tumor growth, reduction of metastases and synergistically decreased JAK2 or FLT signaling, depending on the cellular context. In addition, several plasma cytokines/growth factors/chemokines triggered by the tumor growth were normalized, providing a rationale for combination therapy with an HDACi and a JAK2/FLT3 inhibitor for the treatment of AML patients, particularly those with FLT3 or JAK2 mutations.

Description

Pracinostat is a potent histone deacetylase (HDAC) inhibitor, with IC50s of 40-140 nM, used for cancer research.

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