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

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

Mechanism ad kinetics of acetyl-lysine binding to bromodomains

Bromodomains are four-helix bundle proteins that specifically recognize acetylation of lysine side chains on histones. The available X-ray structures of bromodomain/histone tail complexes show that the conserved Asn residue in the loop between helices B and C is involved in a hydrogen bond with the acetyl-lysine side chain. Here we analyze the spontaneous binding of acetyl-lysine to the bromodomain TAF1(2) by the first molecular dynamics simulations of histone mark binding to an epigenetic reader protein. Multiple events of reversible association sampled along the unbiased simulations allow us to determine the pathway and kinetics of binding. The simulations show that acetyl-lysine has two major binding modes in TAF1(2) one of which corresponds to the available crystal structures and is stabilized by a hydrogen bond to the conserved Asn side chain. The other major binding mode is more buried than in the crystal structures and is stabilized by two hydrogen bonds with conserved residues of the loop between helices Z and A. In the more buried binding conformation, three of the six structured water molecules at the bottom of the binding pocket are displaced by the acetyl-lysine side chain. The kinetic analysis shows that the two binding modes interconvert on a faster time scale with respect to the association/dissociation process. The atomic-level description of the binding pathway and binding modes is useful for the design of small molecule modulators of histone binding to bromodomains