Abexinostat (PCI-24781)

Catalog No.S1090 Batch:S109006

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Technical Data

Formula

C21H23N3O5
Molecular Weight 397.42 CAS No. 783355-60-2
Solubility (25°C)* In vitro 5%TFA 3 mg/mL (7.54 mM)
DMSO Insoluble
Water Insoluble
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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Biological Activity

Description Abexinostat (PCI-24781, CRA-024781) is a novel pan-HDAC inhibitor mostly targeting HDAC1 with Ki of 7 nM, modest potent to HDACs 2, 3, 6, and 10 and greater than 40-fold selectivity against HDAC8. Phase 1/2.
Targets
HDAC1 [1]
(Cell-free assay)		 HDAC3/SMRT [1] HDAC6 [1] HDAC2 [1]
(Cell-free assay)		 HDAC10 [1] View More
7 nM(Ki) 8.2 nM(Ki) 17 nM(Ki) 19 nM(Ki) 24 nM
In vitro PCI-24781 exhibits potent antitumor activity against a variety of tumor cell lines with GI50 ranging from 0.15 μM to 3.09 μM. PCI-24781 also has an antiproliferative effect on HUVEC endothelial cells with GI50 of 0.43 μM. PCI-24781 treatment causes dose-dependent accumulation of both acetylated histones and acetylated tubulin in HCT116 or DLD-1 cells, induces expression of p21, and leads to PARP cleavage and accumulation of the γH2AX. [1] Inhibition of HDAC enzymes by PCI-24781 leads to a significant reduction in the transcription of genes specifically associated with HR, including RAD51. Consistent with inhibition of HR, PCI-24781 treatment results in a decreased ability to perform homology directed repair of I-SceI-induced chromosome breaks in transfected CHO cells. [2] PCI-24781 induces S phase depletion, G2 cell cycle arrest, and apoptosis in soft tissue sarcoma (STS) cells. PCI-24781 induces Rad51 transcriptional repression in STS cells potentially mediated via enhanced E2F1 binding to the Rad51 proximal promoter. [3] PCI-24781 induces caspase and reactive oxygen species-dependent apoptosis through NF-κB mechanisms in Hodgkin lymphoma and non-Hodgkin lymphoma cell lines. [4]
In vivo Administration of PCI-24781 at 200 mg/kg once daily every other day (q.o.d.) significantly inhibits the growth of HCT116 and DLD-1 xenografts in mice by 69% and 59%, respectively. Administration of PCI-24781 at 20 mg/kg, 40 mg/kg, 80 mg/kg, or 160 mg/kg once daily for 4 consecutive days followed by 3 days without treatment each week (q.d. × 4 per week) in the HCT116 model causes inhibition of tumor growth by 48%, 57%, 82.2%, or 80.0%, respectively. [1]

Protocol (from reference)

Kinase Assay:[1]
  • HDAC Activity

    HDAC activity is measured using a continuous trypsin-coupled assay. For inhibitor characterization, measurements are done in a reaction volume of 100 μL using 96-well assay plates. For each isozyme, the HDAC protein in reaction buffer [50 mM HEPES, 100 mM KCl, 0.001% Tween 20, 5% DMSO (pH 7.4), supplemented with bovine serum albumin at concentrations of 0% (HDAC1), 0.01% (HDAC2, 3, 8, and 10), or 0.05% (HDAC6)] is mixed with PCI-24781 at various concentrations and allowed to incubate for 15 minutes. Trypsin is added to a final concentration of 50 nM, and acetyl-Gly-Ala-(N-acetyl-Lys)-AMC is added to a final concentration of 25 μM (HDAC1, 3, and 6), 50 μM (HDAC2 and 10), or 100 μM (HDAC8) to initiate the reaction. Negative control reactions are done in the absence of PCI-24781 in replicates of eight. Reactions are monitored in a fluorescence plate reader. After a 30-minute lag time, the fluorescence is measured over a 30-minute time frame using an excitation wavelength of 355 nm and a detection wavelength of 460 nm. The increase in fluorescence with time is used as the measure of the reaction rate. Inhibition constants Ki(app) are obtained using the program BatchKi.
Cell Assay:[1]
  • Cell lines

    HCT116, HCT-15, BT-549, NCI-H226, CWR-22RV1, MCF-7, NCI-PC3, DLD-1, SKOV-3, and OVCAR-3

  • Concentrations

    Dissolved in DMSO, final concentrations ~10 μM

  • Incubation Time

    48, 72, 96, or 120 hours

  • Method

    Cells are cultured for at least two doubling times, and growth is monitored at the end of PCI-24781 exposure using an Alamar blue fluorometric cell proliferation assay. PCI-24781 is assayed in triplicate wells in 96-well plates at nine concentrations using half-log intervals ranging from 0.0015 μM to 10 μM. The final DMSO concentration in each well is 0.15%. The concentration required to inhibit cell growth by 50% (GI50) and 95% confidence intervals are estimated from nonlinear regression using a four-parameter logistic equation.
Animal Study:[1]
  • Animal Models

    Female BALB/c nu/nu mice implanted s.c. with HCT116 and DLD-1 tumor cells

  • Dosages

    ~200 mg/kg

  • Administration

    Administered via i.v.

Customer Product Validation

Data from [Biochem Bioph Res Co, 2012, 55, 2421-31]

Data from [Nat Biotechnol, 2011, 29, 255-265]

Data from [Biochem Bioph Res Co, 2011, 414, 25-30]

Selleck's Abexinostat (PCI-24781) has been cited by 22 publications

Nuclear oligo hashing improves differential analysis of single-cell RNA-seq [ Nat Commun, 2022, 13(1):2666] PubMed: 35562344
Single-cell profiling-guided combination therapy of c-Fos and histone deacetylase inhibitors in diffuse large B-cell lymphoma [ Clin Transl Med, 2022, 12(5):e798] PubMed: 35522945
Small-molecule inhibitors of histone deacetylase improve CRISPR-based adenine base editing [ Nucleic Acids Res, 2021, 49(4):2390-2399] PubMed: 33544854
Epigenetic targeting of the ACE2 and NRP1 viral receptors limits SARS-CoV-2 infectivity [ Clin Epigenetics, 2021, 13(1):187] PubMed: 34635175
Combining APR-246 and HDAC-Inhibitors: A Novel Targeted Treatment Option for Neuroblastoma [ Cancers (Basel), 2021, 13(17)4476] PubMed: 34503286
Quantifying Drug Combination Synergy along Potency and Efficacy Axes. [ Cell Syst, 2019, 8(2):97-108] PubMed: 30797775
Epigenetic Reprogramming with Antisense Oligonucleotides Enhances the Effectiveness of Androgen Receptor Inhibition in Castration-Resistant Prostate Cancer [ Cancer Res, 2018, 78(20):5731-5740] PubMed: 30135193
Dual role of HDAC10 in lysosomal exocytosis and DNA repair promotes neuroblastoma chemoresistance. [ Sci Rep, 2018, 8(1):10039] PubMed: 29968769
Inhibiting HDAC1 Enhances the Anti-Cancer Effects of Statins through Downregulation of GGTase-Iβ Expression. [ Int J Mol Sci, 2017, 18(5)] PubMed: 28481295
[ Oncoimmunology, 2016, ] PubMed: 27471639

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SHIPPING AND STORAGE
Selleck products are transported at room temperature. If you receive the product at room temperature, please rest assured, the Selleck Quality Inspection Department has conducted experiments to verify that the normal temperature placement of one month will not affect the biological activity of powder products. After collecting, please store the product according to the requirements described in the datasheet. Most Selleck products are stable under the recommended conditions.

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