Mocetinostat (MGCD0103) is a potent HDAC inhibitor with most potency for HDAC1 with IC50 of 0.15 μM in a cell-free assay, 2- to 10- fold selectivity against HDAC2, 3, and 11, and no activity to HDAC4, 5, 6, 7, and 8. Phase 2.
Comparison of MCAS ovarian cancer cells harboring control and CtBP2 knockdown shRNAs for sensitivity to chemotherapeutic agents. For each cell line, the MTT reading of the untreated cells was assigned as 100%. HDAC inhibitors: (a) Trichostatin A; (b) Vorinostat; (c) Belinostat; (d) MGCD0103; (e) valproic acid; and (f ) carboplatin, a non-HDAC inhibitor.
Oncogene 2012 32, 3896-903. Mocetinostat (MGCD0103) purchased from Selleck.
Class-specific histone deacetylase inhibition ameliorates cholesterol accumulation. Mutant fibroblasts (NPC-26) were incubated for 18 h in the presence of the HDAC class-specific inhibitors MC1568 and MGCD0103 (5 μM) and assessed for cholesterol accumulation by filipin fluorescence. Quantification of filipin fluorescence is expressed as arbitrary units. *, p<0.05, treated versus untreated cells by two-tailed Student,s t test.
J Biol Chem 2011 286, 23842–23851. Mocetinostat (MGCD0103) purchased from Selleck.
HDACIs That Simultaneously Inhibit HDACs 1 and 6 Showed Greater Antileukemic Activities than HDACIs that Don,t at Cmax Concentrations. THP-1 cells were treated with LBH-589, PXD101, SAHA, VPA, MS-275 and MGCD0103 at Cmax concentrations for 3 h and 24 h, respectively. The cells post 3 h treatments were washed three times with complete medium and divided into two halves. One half of the cells was resuspended in complete media and cultured for up to 24 h to determine the effects of the 3 h treatments on cell proliferation and apoptosis. The other half of the cells was used to prepare whole cell lysates. Whole cell lysates from the 3 h and 24 h treatments were extracted and subjected to Western blots probed by anti-ac-tubulin or-β-actin antibody (panels A&B), or subjected to HDAC1 enzymatic assays post IP as described in the Materials and Methods (Panels C&D). The effects of the 3 h and 24 h HDACI treatments on cell proliferation, as reflected by percent decrease of live cells relative to untreated cells (panel E), and apoptosis (panel F) were determined by flow cytometry analysis as described in the Materials and Methods.
PLoS One 2011 6, e17138. Mocetinostat (MGCD0103) purchased from Selleck.
Induction of DNA Damage and Bim Is Critical for HDACI-Induced Apoptosis in Pediatric AML Cells. THP-1 cells were treated with the HDACIs at Cmax concentrations for 3 (panel A) and 24 h (panel B), respectively. Whole cell lysates were extracted and subjected to Western blots probed by anti-p21, -c-Myc, -cH2AX, -Bim, or -b-actin antibody.
PLoS One 2011 6, e17138. Mocetinostat (MGCD0103) purchased from Selleck.
HDACI sensitivities in pancreatic cancer cell lines and the HPDE cells. Panels A–C: PANC-1 cells were harvested and lysed after incubation with a range of concentrations of MGCD0103 (0–1.0 uM), MC1568 (0–10 uM), or Tubastatin A (0–4 uM) for 96 h. Soluble proteins were analyzed on Western blots probed by anti-acetylated (ac)-H4, -H4, -ac-tubulin, or –b-actin antibody. Panel D: AsPC-1, BxPC-3, PANC-1, or the HPDE cells were cultured at 37’C for 96 h in complete medium in 96-well plates, with a range of concentrations of MGCD0103, MC1568, or Tubastatin A, and cell viabilities were determined using the MTT reagent.
PLoS One 2012 7, e52095. Mocetinostat (MGCD0103) purchased from Selleck.
|製品説明||Mocetinostat (MGCD0103) is a potent HDAC inhibitor with most potency for HDAC1 with IC50 of 0.15 μM in a cell-free assay, 2- to 10- fold selectivity against HDAC2, 3, and 11, and no activity to HDAC4, 5, 6, 7, and 8. Phase 2.|
MGCD0103 inhibits only a subset of the nine human recombinant HDACs, including HDAC1, HDAC2, HDAC3, and HDAC11 at nanomolar or low micromolar concentrations, in a dose-dependent manner. MGCD0103 reveals most potent inhibitory activity against human HDAC1 and HDAC2 enzymes in vitro, and it does not inhibit class II HDACs. The exocyclic amino group in MGCD0103 is necessary for enzyme inhibitory activity because HDAC-inhibitory activity against HDAC1 and HDAC2 is completely abolished with the desamino analogue. The inhibitory activity of MGCD0103 reaches the maximum plateau at 6 μM, and the maximal inhibitable enzyme pool affected by MGCD0103 is 75% of the total enzyme activity in HCT116 cells whereas NVP-LAQ824 inhibits almost 100% of that in these cells. In A549 cells, MGCD0103 also exhibits dose-dependent inhibition of HDAC activity in whole cells. 
|体内試験||MGCD0103 significantly inhibites growth of human tumor xenografts in nude mice and the antitumor activity correlated with induction of histone acetylation in tumors. P.O. administration of MGCD0103 (2HBr salt) significantly decreases growth of implanted advanced A549 tumors in nude mice in a dose-dependent manner after 13 days of daily administration. MGCD0103 (170 mg/kg for 2HBr salt, corresponding to 120 mg/kg of free base) significantly blockes growth of tumors compared with vehicle treatment alone with no change in body weight. In addition, MGCD0103 does not reduce WBC counts and is well tolerated. MGCD0103 is also orally active in many other human tumor xenograft models including NSCLC H1437. MGCD0103 at 80 mg/kg (free base) almost completely blocks the growth of H1437 tumors after 13 days of daily p.o. administration with no reduction of body weight in animals.  MGCD0103 reduces pulmonary arterial pressure more dramatically than tadalafil, a standard-of-care therapy for human pulmonary hypertension that functions as a vasodilator. Moreover, MGCD0103 improves pulmonary artery acceleration time and reduced systolic notching of the pulmonary artery flow envelope, which suggests a positive impact of the HDAC inhibitor on pulmonary vascular remodeling and stiffening. |
HDAC enzyme assay in vitro:The deacetylase enzyme assay is based on a homogeneous fluorescence release assay. Purified recombinant HDAC enzymes are incubated with MGCD0103 diluted in various concentrations for 10 minutes in assay buffer [25 mM HEPES (pH 8.0), 137 mM NaCl, 1 mM MgCl2, 2.7 mM KCl] at room temperature. The substrate Boc-Lys(ε-Ac)-AMC is added to the reaction for further incubation at 37 °C. The concentration of the substrate and the incubation time varies for different isotypes of HDAC enzymes. A 20-min trypsin incubation at room temperature allows the release of the fluorophore from the deacetylated substrate. The fluorescent signal is detected by fluorometer at excitation of 360 nm, emission of 470 nm, and cutoff at 435 nm.
|体外||DMSO||13 mg/mL (32.79 mM)|
30% PEG400+0.5% Tween80+5% Propylene glycol
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|
|NCT03565406||Recruiting||Melanoma||New York University School of Medicine||April 25 2018||Phase 1|
|NCT02993991||Withdrawn||Squamous Cell Carcinoma Head And Neck|Squamous Cell Carcinoma Mouth|Resectable Squamous Cell Carcinoma of Oral Cavity||University Health Network Toronto|Mirati Therapeutics Inc.|AstraZeneca||October 10 2017||Phase 1|
|NCT03220477||Recruiting||Lung Cancer||Memorial Sloan Kettering Cancer Center|Merck Sharp & Dohme Corp.|Astex Pharmaceuticals|Mirati Therapeutics Inc.|Stand Up To Cancer|Van Andel Research Institute||August 4 2017||Phase 1|
|NCT02954991||Recruiting||Carcinoma Non-Small-Cell Lung||Mirati Therapeutics Inc.||November 2016||Phase 2|
|NCT02805660||Recruiting||Advanced Cancer||Mirati Therapeutics Inc.||May 2016||Phase 1|Phase 2|
|NCT02303262||Completed||Metastatic Leiomyosarcoma||Sarcoma Alliance for Research through Collaboration||September 2015||Phase 2|