PCI-24781 (Abexinostat)

Catalog No.S1090

PCI-24781 (Abexinostat) 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.

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PCI-24781 (Abexinostat) Chemical Structure

PCI-24781 (Abexinostat) Chemical Structure
Molecular Weight: 397.42

Validation & Quality Control

3 customer reviews :

Quality Control & MSDS

Related Compound Libraries

PCI-24781 (Abexinostat) is available in the following compound libraries:

HDAC Inhibitors with Unique Features

Product Information

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  • Combination Therapy
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Product Description

Biological Activity

Description PCI-24781 (Abexinostat) 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] HDAC3/SMRT [1] HDAC6 [1] HDAC2 [1]

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IC50 7 nM(Ki) 8.2 nM(Ki) 17 nM(Ki) 19 nM(Ki)
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]
Features

Protocol(Only for 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
Formulation Formulated in 30% HP-cyclodextrin in water
Dosages ~200 mg/kg
Administration Administered via i.v.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Buggy JJ, et al. Mol Cancer Ther, 2006, 5(5), 1309-1317.

[2] Adimoolam S, et al. Proc Natl Acad Sci U S A, 2007, 104(49), 19482-19487.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-06-25)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT01543763 Recruiting Metastatic Solid Tumors University of California, San Francisco|GlaxoSmithKline|P  ...more University of California, San Francisco|GlaxoSmithKline|Pharmacyclics May 2012 Phase 1
NCT01149668 Completed Lymphoma|Non-Hodgkins Lymphoma|Hodgkin Disease|Multiple Myeloma|Leukemia|Lymphocytic Pharmacyclics June 2010 Phase 1
NCT01027910 Completed Sarcoma Massachusetts General Hospital|Dana-Farber Cancer Institu  ...more Massachusetts General Hospital|Dana-Farber Cancer Institute|Brigham and Womens Hospital|Pharmacyclics February 2009 Phase 1|Phase 2
NCT00724984 Completed Lymphoma|Hodgkin Disease|Lymphoma, Non-Hodgkin Pharmacyclics July 2008 Phase 1|Phase 2
NCT00562224 Completed Neoplasms by Site|Lymphoma, Non-hodgkin|Hodgkin Disease|Multiple Myeloma|Leukemia, Lymphocytic, Chronic Pharmacyclics November 2007 Phase 1

Chemical Information

Download PCI-24781 (Abexinostat) SDF
Molecular Weight (MW) 397.42
Formula

C21H23N3O5

CAS No. 783355-60-2
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms CRA-024781
Solubility (25°C) * In vitro DMSO 80 mg/mL (201.29 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
* <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.
Chemical Name 3-((dimethylamino)methyl)-N-(2-(4-(hydroxycarbamoyl)phenoxy)ethyl)benzofuran-2-carboxamide

Customer Product Validation(3)


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Rating
Source Nat Biotechnol 2011 29, 255-265. PCI-24781 (Abexinostat) purchased from Selleck
Method Immunofluorescence
Cell Lines K562 cells
Concentrations 2 μM
Incubation Time 6 h
Results The nonselective HDAC inhibitors (SAHA, PCI-24781) increased steady-state acetylation of tubulin and histones manifested by the staining of acetylated microtubules and punctuate nuclear staining of acetylated histones. The class I selective HDAC inhibitors stimulated histone acetylation but did not affect tubulin.

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Rating
Source Biochem Bioph Res Co 2012 55, 2421-31. PCI-24781 (Abexinostat) purchased from Selleck
Method Cell viability assay
Cell Lines INS-1 cells
Concentrations 16-80 h
Incubation Time
Results CI-994, PCI24781 and LAQ824 all protected against cytokine-induced beta cell death, whereas the HDAC8-selective inhibitor PCI34051 showed no protection.

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Rating
Source Biochem Bioph Res Co 2011 414, 25-30. PCI-24781 (Abexinostat) purchased from Selleck
Method Analyses of efficacy, potency and IC50
Cell Lines INS-1 cells
Concentrations
Incubation Time
Results HC toxin, CI-994, PCI24781 and LAQ824 all protected against cytokine-induced beta cell death, whereas the HDAC8-selective inhibitor PCI34051 showed no protection.

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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