Antibodies
PCI-24781 (Abexinostat)
- 貨號 Cat. No.
- S1090
- 規格 Size
- 5~200mg
- 品牌 Brand
- Selleckchem
Description
PCI-24781 (Abexinostat)
PCI-24781 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.
| Size | Price | Stock | Quantity | ||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| |||||||||||||||||||||||
Distributor Tel: +886-2-2827-1197jimmy@new.abscience.com.tw
Biological Activity
| Description | PCI-24781 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 | HDAC2 | HDAC3 | HDAC6 | HDAC8 | HDAC10 |
| IC50 | 7 nM (Ki) | 19 nM (Ki) | 8.2 nM (Ki) | 17 nM (Ki) | 280 nM (Ki) | 24 nM (Ki) [1] |
| 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 |
|---|---|
| Dosages | ~200 mg/kg |
| Administration | Administered via i.v. |
References
Clinical Trial Information( data from http://clinicaltrials.gov)
| NCT Number | Recruitment | Conditions | Sponsor /Collaborators | Start Date | Phases |
|---|---|---|---|---|---|
| NCT00562224 | Completed | Neoplasms by Site|Lymphoma, Non-hodgkin|Hodgkin Disease|Multiple Myeloma|Leukemia, Lymphocytic, Chronic | Pharmacyclics | 2007-11 | Phase 1 |
| NCT00724984 | Active, not recruiting | Lymphoma|Hodgkin Disease|Lymphoma, Non-Hodgkin | Pharmacyclics | 2008-07 | Phase 1|Phase 2 |
| NCT01027910 | Active, not recruiting | Sarcoma | Massachusetts General Hospital|Dana-Farber Cancer Institute|Brigham and Women’s Hospital|Pharmacyclics | 2009-02 | Phase 1|Phase 2 |
| NCT01149668 | Active, not recruiting | Lymphoma|Non-Hodgkin’s Lymphoma|Hodgkin Disease|Multiple Myeloma|Leukemia|Lymphocytic|Chronic | Pharmacyclics | 2010-06 | Phase 1 |
| NCT01543763 | Recruiting | Metastatic Solid Tumors | University of California, San Francisco|GlaxoSmithKline|Pharmacyclics | 2012-05 | 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 DMSO | |
| Syonnyms | CRA-02478 |
| Solubility (25°C) * | In vitro | DMSO | 80 mg/mL (201 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 Reviews (3)
 Click to enlarge | Rating | |
| Source | Diabetologia, 2012, 55, 2421–2431. 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. |
Product Citations (4)
Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes. [Bantscheff M, et al. Nat Biotechnol 2011;29(3):255-65]
The Narrow-Spectrum HDAC Inhibitor Entinostat Enhances NKG2D Expression Without NK Cell Toxicity, Leading to Enhanced Recognition of Cancer Cells. [Zhu S, et al. Pharm Res 2013;10.1007/s11095-013-1231-0]
MSH3 Mismatch Repair Protein Regulates Sensitivity to Cytotoxic Drugs and a Histone Deacetylase Inhibitor in Human Colon Carcinoma Cells. [Park JM, et al. PLoS One 2013;8(5):e65369]
