Although clinical responses in liquid tumors and certain lymphomas have been reported, the clinical efficacy of histone deacetylase inhibitors in solid tumors has been limited. This may be in part due to the poor pharmacokinetic of these drugs, resulting in inadequate tumor concentrations of the drug. SB939 is a new hydroxamic acid based histone deacetylase inhibitor with improved physicochemical, pharmaceutical, and pharmacokinetic properties. In vitro, SB939 inhibits class I, II, and IV HDACs, with no effects on other zinc binding enzymes, and shows significant antiproliferative activity against a wide variety of tumor cell lines. It has very favorable pharmacokinetic properties after oral dosing in mice, with >4-fold increased bioavailability and 3.3-fold increased half-life over suberoylanilide hydroxamic acid (SAHA). In contrast to SAHA, SB939 accumulates in tumor tissue and induces a sustained inhibition of histone acetylation in tumor tissue. These excellent pharmacokinetic properties translated into a dose-dependent antitumor efficacy in a xenograft model of human colorectal cancer (HCT-116), with a tumor growth inhibition of 94% versus 48% for SAHA (both at maximum tolerated dose), and was also effective when given in different intermittent schedules. Furthermore, in APC min mice, a genetic mouse model of early-stage colon cancer, SB939 inhibited adenoma formation, hemocult scores, and increased hematocrit values more effectively than 5-fluorouracil. Emerging clinical data from phase I trials in cancer patients indicate that the pharmacokinetic and pharmacologic advantages of SB939 are translated to the clinic. The efficacy of SB939 reported here in two very different models of colorectal cancer warrants further investigation in patients. Mol Cancer Ther; 9(3); 642-52. ©2010 AACR.

Metal−organic frameworks (MOFs) are composed of metal ions/clusters and organic ligands, showing accessible functional sites, ultra-high porosity, and large specific surface area. Tricopper benzene-1,3,5-tricarboxylate (CuBTC), as a three-dimensional MOF architecture with an open and robust micro-/nanoconfiguration, possesses excellent catalytic performance and superior electric conductivity as compared to bulk MOF. In this study, CuBTC was used as a substrate on which molybdenum disulfide (MoS 2 ) was in situ constructed by a hydrothermal reaction to enhance the electronand ion-transfer capability. Then, gold nanoparticles (AuNPs) were electroreduced on a CuBTC@MoS 2 -modified electrode by linear sweep voltammetry for strengthening the connection between CA125 antibodies (CA125 Ab) and the substrate material. Due to the synergistic effect of CuBTC@MoS 2 and AuNPs, our biosensor showed excellent electrochemical performance. Subsequently, CuBTC@MoS 2 -AuNPs/CA125 Ab-functionalized electrodes were used for the detection of the ovarian cancer biomarker CA125 from 0.5 mU/mL to 500 U/mL by differential pulse voltammetry. The results showed that the peak current decreased with the increase of concentration, and there was a logistic regression relationship between peak current variation and concentration. As interfering substances, carcinoembryonic antigen, human epididymis protein 4, and bovine serum albumin were applied for specific analysis. Our biosensor showed an obviously large response signal for CA125 detection than those observed for other interfering substances. Finally, serum samples collected from five patients were tested on our sensors with good consistency toward clinical standards, showing high practicability. This work demonstrated a tactic for simultaneously integrating the nanostructure, electroconductivity, and biocompatibility to construct advanced biosensors for cancer biomarkers.

ABSTRACT:The preclinical absorption, distribution, metabolism, and excretion (ADME) properties of Pracinostat [(2E)-3-[2-butyl-1-[2-(diethylamino) ethyl]-1H-benzimidazol-5-yl]-N-hydroxyarylamide hydrochloride; SB939], an orally active histone deacetylase inhibitor, were characterized and its human pharmacokinetics (PK) was predicted using Simcyp and allometric scaling. SB939 showed high aqueous solubility with high Caco-2 permeability. Metabolic stability was relatively higher in dog and human liver microsomes than in mouse and rat. The major metabolites formed in human liver microsomes were also observed in preclinical species. Human cytochrome P450 (P450) phenotyping showed that SB939 was primarily metabolized by CYP3A4 and CYP1A2. SB939 did not significantly inhibit human CYP3A4, 1A2, 2D6, and 2C9 (>25 M) but inhibited 2C19 (IC 50 ‫؍‬ 5.8 M). No significant induction of human CYP3A4 and 1A2 was observed in hepatocytes. Plasma protein binding in mouse, rat, dog, and human ranged between ϳ84 and 94%. The blood-toplasma ratio was ϳ1.0 in human blood. SB939 showed high systemic clearance (relative to liver blood flow) of 9.2, 4.5, and 1.5 l ⅐ h ؊1 ⅐ kg ؊1 and high volume of distribution at steady state (>0.6 l/kg) of 3.5, 1.7, and 4.2 l/kg in mouse, rat, and dog, respectively. The oral bioavailability was 34, 65, and ϳ3% in mice, dogs, and rats, respectively. The predicted oral PK profile and parameters of SB939, using Simcyp and allometric scaling, were in good agreement with observed data in humans. Simcyp predictions showed lack of CYP3A4 and 2C19 drug-drug interaction potential for SB939. In summary, the preclinical ADME of SB939 supported its preclinical and clinical development as an oral drug candidate.

No abstract