Small molecule inhibition of protein depalmitoylation as a new approach towards downregulation of oncogenic Ras signalling

AbstractThe H- and N-Ras GTPases are prominent examples of proteins, whose localizations and signalling capacities are regulated by reversible palmitoylations and depalmitoylations. Recently, the novel small molecule inhibitor palmostatin B has been described to inhibit Ras depalmitoylation and to revert the phenotype of oncogenic HRasG12V transformed cells. This demonstrates that palmostatin B is a tool to investigate the biochemical effects of the inhibition of cellular Ras depalmitoylation on Ras signalling, which is relevant for oncology. Furthermore, it is to be expected that many proteins, of which the signalling capacities depend on reversible palmitoylation, will be discovered in the near future. This stresses the urgent need for further development of small molecule inhibitors of palmitoylation and depalmitoylation in order to study their functions in cellular signalling

Novel Design Strategies to Enhance the Efficiency of Proteolysis Targeting Chimeras

Despite the success of drug discovery over the past decades, many potential drug targets still remain intractable for small molecule modulation. The development of proteolysis targeting chimeras (PROTACs) that trigger degradation of the target proteins provides a conceptually novel approach to address drug targets that remained previously elusive. Currently, the main challenge of PROTAC development is the identification of efficient, tissue- and cell-selective PROTAC molecules with good drug-likeness and favorable safety profiles. This review focuses on strategies to enhance the effectiveness and selectivity of PROTACs. We provide a comprehensive summary of recently reported PROTAC design strategies and discuss the advantages and disadvantages of these strategies. Future perspectives for PROTAC design will also be discussed

Histone acetyltransferases:challenges in targeting bi-substrate enzymes

Histone acetyltransferases (HATs) are epigenetic enzymes that install acetyl groups onto lysine residues of cellular proteins such as histones, transcription factors, nuclear receptors, and enzymes. HATs have been shown to play a role in diseases ranging from cancer and inflammatory diseases to neurological disorders, both through acetylations of histone proteins and non-histone proteins. Several HAT inhibitors, like bi-substrate inhibitors, natural product derivatives, small molecules, and protein-protein interaction inhibitors, have been developed. Despite their potential, a large gap remains between the biological activity of inhibitors in in vitro studies and their potential use as therapeutic agents. To bridge this gap, new potent HAT inhibitors with improved properties need to be developed. However, several challenges have been encountered in the investigation of HATs and HAT inhibitors that hinder the development of new HAT inhibitors. HATs have been shown to function in complexes consisting of many proteins. These complexes play a role in the activity and target specificity of HATs, which limits the translation of in vitro to in vivo experiments. The current HAT inhibitors suffer from undesired properties like anti-oxidant activity, reactivity, instability, low potency, or lack of selectivity between HAT subtypes and other enzymes. A characteristic feature of HATs is that they are bi-substrate enzymes that catalyze reactions between two substrates: the cofactor acetyl coenzyme A (Ac-CoA) and a lysine-containing substrate. This has important-but frequently overlooked-consequences for the determination of the inhibitory potency of small molecule HAT inhibitors and the reproducibility of enzyme inhibition experiments. We envision that a careful characterization of molecular aspects of HATs and HAT inhibitors, such as the HAT catalytic mechanism and the enzyme kinetics of small molecule HAT inhibitors, will greatly improve the development of potent and selective HAT inhibitors and provide validated starting points for further development towards therapeutic agents.</p

Epigenetic regulation in macrophage migration inhibitory factor (MIF)-mediated signaling in cancer and inflammation

Epigenetic mechanisms are important for the regular development and maintenance of the tissue-specific expression of cytokine genes. One of the crucial cytokines involved in cancer and inflammation is macrophage migration inhibitory factor (MIF), which triggers the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling pathways by binding to CD74 and other receptors. Altered expression of this cytokine and altered activity states of the connected pathways are linked to inflammatory disease and cancer. Therapeutic strategies based on epigenetic mechanisms have the potential to regulate MIF-mediated signaling in cancer and inflammation

The Process and Strategy for Developing Selective Histone Deacetylase 3 Inhibitors

Histone deacetylases (HDACs) are epigenetic drug targets that have gained major scientific attention. Inhibition of these important regulatory enzymes is used to treat cancer, and has the potential to treat a host of other diseases. However, currently marketed HDAC inhibitors lack selectivity for the various HDAC isoenzymes. Several studies have shown that HDAC3, in particular, plays an important role in inflammation and degenerative neurological diseases, but the development of selective HDAC3 inhibitors has been challenging. This review provides an up-to-date overview of selective HDAC3 inhibitors, and aims to support the development of novel HDAC3 inhibitors in the future

Kansen voor ’t Gorechthuis:’t Gorechthuis op eigen benen

De Gereformeerde Kerk in Haren beheert en exploiteert 't Gorechthuis, het is onderdeel van het complex mede bestaande uit de Gorechtkerk en jeugdgebouw 't Schip. Het College van Kerkrentmeesters is verantwoordelijk voor het beheer en de exploitatie van dit complex. Zij heeft geconstateerd dat de kosten van beheer en exploitatie stijgen en dat de inkomsten onvoldoende stijgen. De beheerders van ’t Gorechthuis willen graag weten op welke manier zij meer inkomsten kunnen genereren en of de manier waarop zij nu te werk gaan wel rendabel genoeg is. De vraagstelling die de Commissie Gorecht heeft is: Op welke manier kunnen er hogere inkomsten gegenereerd worden voor ´t Gorechthuis? Aansluitend op de vraagstelling die de Commissie Gorecht heeft geformuleerd is er voor het vooronderzoek de volgende vraagstelling geformuleerd: Wat is op dit moment de huidige situatie van ’t Gorechthuis? Het doel van het vooronderzoek is om de commissie Gorecht inzicht te geven in de tevredenheid van de gebruikers van ’t Gorechthuis. Hierdoor wordt duidelijk wat de plus en –minpunten zijn van ’t Gorechthuis. Op deze manier kan ’t Gorechthuis enkele veranderingen doorvoeren en hierdoor wordt de bezettingsgraad verhoogd. Studentonderzoek in het kader van het thema Leefomgevin

Targeting HDAC Complexes in Asthma and COPD

Around three million patients die due to airway inflammatory diseases each year. The most notable of these diseases are asthma and chronic obstructive pulmonary disease (COPD). Therefore, new therapies are urgently needed. Promising targets are histone deacetylases (HDACs), since they regulate posttranslational protein acetylation. Over a thousand proteins are reversibly acetylated, and acetylation critically influences aberrant intracellular signaling pathways in asthma and COPD. The diverse set of selective and non-selective HDAC inhibitors used in pre-clinical models of airway inflammation show promising results, but several challenges still need to be overcome. One such challenge is the design of HDAC inhibitors with unique selectivity profiles, such as selectivity towards specific HDAC complexes. Novel strategies to disrupt HDAC complexes should be developed to validate HDACs further as targets for new anti-inflammatory pulmonary treatments

Rational Design in Photopharmacology with Molecular Photoswitches

Photopharmacology is an attractive approach for achieving targeted drug action with the use of light. In photopharmacology, molecular photoswitches are introduced into the structure of biologically active small molecules to allow for the optical control of their potency. Going beyond trial and error, photopharmacology has progressively applied rational drug design methodologies to devise light-controlled bioactive ligands. In this review, we categorize photopharmacological efforts from the standpoint of medicinal chemistry strategies, focusing on diffusible photochromic ligands modified with photoswitches that operate through E-Z bond isomerization. In the vast majority of cases, photoswitchable ligands are designed as analogs of existing compounds, through a variety of approaches. By analyzing in detail a comprehensive list of instructive examples, we describe the state of the art and discuss future opportunities for rational design in photopharmacology.</p