Pyrido- and benzisothiazolones as inhibitors of histone acetyltransferases (HATs)

Histone acetyltransferases (HATs) are interesting targets for the treatment of cancer and HIV infections but reports on selective inhibitors are very limited. Here we report structure–activity studies of pyrido- and benzisothiazolones in the in vitro inhibition of histone acetyltransferases, namely PCAF, CBP, Gcn5 and p300 using a heterogeneous assay with antibody mediated quantitation of the acetylation of a peptidic substrate. Dependent on the chemical structure distinct subtype selectivity profiles can be obtained. While N-aryl derivatives usually are rather pan-HAT inhibitors, N-alkyl derivatives show mostly a preference for CBP/p300. Selected compounds were also shown to be inhibitors of MOF. The best inhibitors show submicromolar inhibition of CBP. Selected compounds affect growth of HL-60 leukemic cells and LNCaP prostate carcinoma cells with higher potency on the leukemic cells. Target engagement was shown with reduction of histone acetylation in LNCaP cells

The discovery of I-BRD9, a selective cell active chemical probe for bromodomain containing protein 9 inhibition

Acetylation of histone lysine residues is one of the most well-studied post-translational modifications of chromatin, selectively recognized by bromodomain “reader” modules. Inhibitors of the bromodomain and extra terminal domain (BET) family of bromodomains have shown profound anticancer and anti-inflammatory properties, generating much interest in targeting other bromodomain-containing proteins for disease treatment. Herein, we report the discovery of I-BRD9, the first selective cellular chemical probe for bromodomain-containing protein 9 (BRD9). I-BRD9 was identified through structure-based design, leading to greater than 700-fold selectivity over the BET family and 200-fold over the highly homologous bromodomain-containing protein 7 (BRD7). I-BRD9 was used to identify genes regulated by BRD9 in Kasumi-1 cells involved in oncology and immune response pathways and to the best of our knowledge, represents the first selective tool compound available to elucidate the cellular phenotype of BRD9 bromodomain inhibition

Overlapping political budget cycles in the legislative and the executive

We advance the literature on political budget cycles by testing separately for cycles in expenditures for elections in the legislative and the executive. Using municipal data, we can separately identify these cycles and account for general year effects. For the executive branch, we show that it is important whether the incumbent re-runs. To account for the potential endogeneity associated with this decision, we apply a unique instrumental variables approach based on age and pension eligibility rules. We find sizable and significant effects in expenditures before council elections and before joint elections when the incumbent re-runs

Small molecules, big targets: drug discovery faces the protein-protein interaction challenge.

Protein-protein interactions (PPIs) are of pivotal importance in the regulation of biological systems and are consequently implicated in the development of disease states. Recent work has begun to show that, with the right tools, certain classes of PPI can yield to the efforts of medicinal chemists to develop inhibitors, and the first PPI inhibitors have reached clinical development. In this Review, we describe the research leading to these breakthroughs and highlight the existence of groups of structurally related PPIs within the PPI target class. For each of these groups, we use examples of successful discovery efforts to illustrate the research strategies that have proved most useful.JS, DES and ARB thank the Wellcome Trust for funding.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nrd.2016.2

Study of the Thermal Mode of a Barn for Piglets and a Sow, Created by Combined Heating System

The present research addresses solution to the relevant problem of energy efficient heating supply of pig farms with barns of pigs and a sow by applying combined heating systems based on local heating of places for animal keeping. A physical model is developed, which offered the possibility to carry out a complex of experimental studies on determining temperature mode in the barn for piglets and a sow. We established the patterns of influence of thermal capacity of individual heating devices, in particular the heating panel in the place of sow keeping, as well as the heating mat and the infrared heater, on the thermal condition of specific areas.Assessment of the influence of the main factors of the research on its original characteristics was performed. We obtained the equation for determining relative air temperature in the zone of piglets and sow keeping, which depends on relative height of the operation area at a variable air velocity, as well as on incoming air temperature, influenced by the number of animals and background temperature in the premises. Graphical dependences were constructed and empirical dependences were derived based on the conducted experimental studies that can be used in subsequent engineering calculations.Based on the obtained results, we compiled recommendations on the choice of thermotechnical parameters of heating devices, particularly their geometric dimensions, material and method of location of heating elements

Saving electricity and reducing GHG emissions with ECM furnace motors: results from the CCHT and projections to various houses and locations

Two identical houses, a test house and a reference house, were used to compare the effects of energy efficient furnace motors on electricity and natural gas use by replacing the standard motor furnace in the test house with an electronically commutated motor (ECM). Electricity and natural gas use was assessed for a wide range of space heating and air conditioning weather for both continuous and non-continuous circulation. The HOT2000 energy simulation model was used to project the annual energy savings of energy-efficient furnace motors for a variety of houses and climates.On a utilis\ue9 deux (2) habitations de construction identique, soit une maison exp\ue9rimentale et une maison de contr\uf4le, dans le but de comparer les incidences sur la consommation d'\ue9lectricit\ue9 et de gaz naturel qu'ont les moteurs d'appareils de chauffage \ue9conerg\ue9tiques, en rempla\ue7ant le moteur standard de la maison exp\ue9rimentale par un moteur \ue0 commutation \ue9lectronique (MCE). La consommation d'\ue9lectricit\ue9 et de gaz naturel a \ue9t\ue9 \ue9valu\ue9e relativement \ue0 une vaste gamme de conditions climatiques li\ue9es au chauffage et \ue0 la climatisation des b\ue2timents, en mode de circulation tant continue que non continue. Le mod\ue8le de simulation \ue9nerg\ue9tique HOT2000 a \ue9t\ue9 utilis\ue9 aux fins de la projection des \ue9conomies d'\ue9nergie annuelles r\ue9alis\ue9es gr\ue2ce aux moteurs d'appareils de chauffage \ue9conerg\ue9tiques, pour divers types d'habitations et sous divers climats.Peer reviewed: YesNRC publication: Ye

Diminished Sensitivity of Chronic Lymphocytic Leukemia Cells to ABT-737 and ABT-263 Due to Albumin Binding in Blood

Purpose: Inhibition of the antiapoptotic BCL2 family is one of the most promising areas of anticancer drug development. However, ABT-737, a specific BCL2 inhibitor, is neither orally bioavailable nor metabolically stable. To overcome these problems, the structurally related molecule ABT-263 was synthesized and recently entered clinical trials in hematologic malignancies, including chronic lymphocytic leukemia (CLL). Almost all laboratory studies have been carried out with ABT-737 rather than ABT-263, the drug being used in clinical trials. Currently there are no published data on the comparative effects of these inhibitors. To gain insight into the potential value or limitations of ABT-263 in the clinic, we assessed its ability to induce apoptosis in clinically relevant cellular models of CLL. Experimental Design: The susceptibility of freshly isolated primary CLL cells to these inhibitors was compared in standard culture conditions and in conditions that more closely mimic in vivo conditions in a whole blood assay system. Results: ABT-737 was more potent than ABT-263 at inducing apoptosis in CLL cells. In whole blood, ∼100-fold higher concentrations of both drugs were required to induce apoptosis. We found that ABT-263 was highly bound by albumin and that an increased albumin binding of ABT-263 as compared with ABT-737 accounted for the differential sensitivity of CLL cells. Conclusions: Our data indicate that the exquisite in vitro sensitivity of CLL cells to BCL2 inhibitors may be lost in vivo due to high cell densities and the albumin binding of ABT-263. Modification of ABT-263 may yield a BCL2 inhibitor with greater bioavailability and more favorable pharmacokinetics