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.
Differential effects of HDAC inhibitors on histone and tubulin acetylation. Immunofluorescence analysis of histone H3 (K9ac/K14ac) and tubulin acetylation in HeLa cells treated for 4 h with vehicle, SAHA (10 μM), tacedinaline (50 μM), PCI-24781 (20 μM. (a) Mapping of histone acetylation in K562 cells treated with HDAC inhibitors by LC-MS/MS. Cells were treated with TSA (10 μM), SAHA (5 μM), PCI-24781 (2 μM), tacedinaline (50 μM) for 6 h. Histones were extracted from cells and acetylated peptides were quantified after isobaric tagging.
Nat Biotechnol 2011 29, 255-265. Abexinostat (PCI-24781) purchased from Selleck.
Analyses of efficacy, potency and IC50 of HDAC inhibitors point toward HDACs 1–3 as relevant candidates for beta cell protection. Ranking and raw data on ITF drugs (Table 3) and commercial HDAC inhibitors (Table 4) underlying the heat maps of Fig. 1 (A and B). The HDAC inhibitor compounds were tested using a HDAC activity kit and recombinant proteins to determine IC50 values on each individual HDAC (right part of the table). Each drug was further tested using Real-Time Cell Analysis (RTCA) to score their maximal effective concentration (ECmax) as well as the corresponding rescue percentage of cytokine treated INS-1 cells. The drugs were ranked according to % rescue. * DMSO alone controls were included in each experiment, but not shown here. The results indicate that the highest concentrations of DMSO used here (1:1,000) were slightly potentiating the proliferation of the cells. The effects observed in this group of compounds were ascribed to the DMSO.?
Biochem Bioph Res Co 2011 414, 25-30. Abexinostat (PCI-24781) purchased from Selleck.
Class I selective HDACi have the highest INS-1 rescue potential . INS-1 cells were monitored using the real-time xCELLigence system h and the impedance (cell adhesion) was measured as a surrogate of cell viability (cell index) as described in the Methods. (a ) The impedance of duplicates of control (green line), cytokine-exposed (red line) and cytokine+ITF-J-exposed INS-1 cells (blue line) was followed from the start of exposure (indicated by the arrow). Heat maps of 13 different ITF HDAC inhibitor compounds ( b )orsix different commercial HDAC inhibitor compounds (c) were made based on their IC50 values towards selected HDACs . The HDACi inhibitors are ranked after rescue potential according to ESM Tables 1, 2 .( c) Values are corrected for differences in potency since they varied from 33.3 (CI-994) to 0.041 (LAQ824). (d ) Colour code for both heat maps: low IC50 values coloured red, intermediate IC50 values coloured black and high IC50 values coloured blue; grey indicates undetermined IC50.
Biochem Bioph Res Co 2012 55, 2421-31. Abexinostat (PCI-24781) purchased from Selleck.
|製品説明||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.|
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.  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.  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.  PCI-24781 induces caspase and reactive oxygen species-dependent apoptosis through NF-κB mechanisms in Hodgkin lymphoma and non-Hodgkin lymphoma cell lines. 
|体内試験||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. |
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.
|体外||DMSO||80 mg/mL (201.29 mM)|
質量 (g) = 濃度 (mol/L) x 体積 (L) x 分子量 (g/mol)
開始濃度 x 開始体積 = 最終濃度 x 最終体積
この方程式は、一般に略語を使われます：C1V1 = C2V2 ( 入力 出力 )
チップス: 化学式は大文字と小文字の区別ができます。C10H16N2O2 c10h16n2o2
|NCT Number||Recruitment||Conditions||Sponsor/Collaborators||Start Date||Phases|
|NCT03600441||Recruiting||Follicular Lymphoma||Xynomic Pharmaceuticals Inc.||November 30 2018||Phase 2|
|NCT03592472||Recruiting||Renal Cell Carcinoma||Xynomic Pharmaceuticals Inc.||July 17 2018||Phase 3|
|NCT03590054||Recruiting||Stage III Cutaneous Melanoma|Stage IV Cutaneous Melanoma|Locally Advanced Melanoma|Locally Advanced Solid Neoplasm|Metastatic Head and Neck Squamous Cell Carcinoma|Metastatic Malignant Solid Neoplasm|Metastatic Melanoma|Metastatic Urothelial Carcinoma|Non-Small Cell Lung Carcinoma|Stage IB Lung Cancer AJCC v7|Stage III Cutaneous Squamous Cell Carcinoma of the Head and Neck AJCC v8|Stage III Lung Cancer AJCC v8|Stage III Ureter Cancer AJCC v8|Stage IIIA Lung Cancer AJCC v8|Stage IIIB Lung Cancer AJCC v8|Stage IIIC Lung Cancer AJCC v8|Stage IV Cutaneous Squamous Cell Carcinoma of the Head and Neck AJCC v8|Stage IV Lung Cancer AJCC v8|Stage IV Ureter Cancer AJCC v8|Stage IVA Lung Cancer AJCC v8|Stage IVB Lung Cancer AJCC v8||Rahul Aggarwal|Xynomic Pharmaceuticals Inc.|University of California San Francisco||July 19 2018||Phase 1|
|NCT01543763||Active not recruiting||Metastatic Solid Tumors||University of California San Francisco|Pharmacyclics LLC.|Novartis||May 2012||Phase 1|
|NCT01149668||Completed||Lymphoma|Non-Hodgkin''s Lymphoma|Hodgkin Disease|Multiple Myeloma|Leukemia|Lymphocytic||Pharmacyclics LLC.||June 2010||Phase 1|
|NCT01027910||Completed||Sarcoma||Massachusetts General Hospital|Dana-Farber Cancer Institute|Brigham and Women''s Hospital|Pharmacyclics LLC.||February 2009||Phase 1|Phase 2|