info@epichembio.eu + 34 986 812 316

Dekker Group. Medicinal Chemistry.

f.j.dekker@rug.nl
www.rug.nl/staff/f.j.dekker/
Address
Groningen Research Institute of Pharmacy Antonius Deusinglaan 1 9713 AV Groningen The Netherlands
Netherlands
Keywords

histone acetylation inflammation small molecule inhibitors lipoxygenases lysine demethylases

Models

airway inflammation

Techniques

organic chemistry protein expression enzyme inhibition cell cultures

Collaborations outside COST

K. Piwocka, Nencki Institute, Warsaw, Poland

Short description of ongoing research projects

Expanding the molecular toolbox in anti-inflammatory drug discovery Chronic inflammatory diseases, such as asthma, afflict millions of people worldwide. Nevertheless, the molecular mechanisms that drive inflammation remain poorly understood. The activities of enzymes that regulate inflammatory pathways are poorly studied, due to a lack of convenient tools for modulation and detection. It becomes increasingly clear that the slow advance in development of chemistry-based methods to study enzyme activity in its physiological context delays the progress in drug discovery. To address this problem further, I will develop small molecule inhibitors and chemistry-based detection methods to study two enzyme classes that regulate inflammatory responses via nuclear factor kB (NF kB). Inhibitor selectivity between both enzyme classes proved to be important. Firstly, I aim to address histone acetyltransferases (HATs), which stimulate the NF-kB signaling pathway. I will develop the first inhibitors of the HAT Tip60 that are active in cells and can ultimately be applied in clinical studies. In addition, I aim to develop a novel bioorthogonal ligation strategy to study inhibition of histone acetylation in cells to complement the alkyne to azide ‘click’ reaction. Secondly, I aim to study Lipoxygenases (LOXs), which are expressed by NF-kB mediated gene transcription and stimulate this pathway, in a positive feedback loop. I will develop inhibitors to suppress 5-LOX mediated inflammatory responses that are potently active in cells, which will be studied by newly developed probes for activity-based LOX labeling. Ultimately, these small molecule inhibitors and detection methods open up opportunities for drug discovery programs aimed at epigenetic regulation and lipid signaling in NF-kB mediated inflammation. Novel tools to read and write the epigenetic code in inflammation Protein acetylations at lysine residues have a broad regulatory scope. Acetylations of histones form a major part of the histone code for epigenetic regulation of gene-transcription. In addition, reversible acetylations of non-histone proteins proved to be crucial for regulation of nuclear factor kB (NF kB) mediated gene transcription. I aim to study the role of acetylations of histones and other proteins in NF kB mediated gene transcription. Firstly, I will develop a novel bioorthogonal ligation strategy for chemical labeling of protein acetylation in cells. Secondly, I will systematically investigate changes in protein acetylation in response to activation of the NF kB pathway using a proteomics strategy. Thirdly, I will develop small molecule inhibitors of acetyltransferases and study their impact on acetylations that regulate the NF kB signaling pathway. Ultimately, these newly developed detection methods and small molecule inhibitors open up opportunities for drug discovery aimed at epigenetic regulation of NF kB mediated inflammation.

Publications
  1. Eleftheriadis N, Neochoritis CG, Leus NG, van der Wouden PE, Dömling A, Dekker FJ. Rational Development of a Potent 15-Lipoxygenase-1 Inhibitor with in Vitro and ex Vivo Anti-inflammatory Properties. J Med Chem. 2015, accepted
  2. Ourailidou ME, Dockerty P, Witte M, Poelarends GJ, Dekker FJ. Metabolic alkene labeling and in vitro detection of histone acylation via the aqueous oxidative Heck reaction. Org Biomol Chem. 2015, 13(12), 3648-53.
  3. Dekker FJ, van den Bosch T, Martin NI. Small molecule inhibitors of histone acetyltransferases and deacetylases are potential drugs for inflammatory diseases. Drug Discov Today. 2014, 19(5), 654-60.
  4. Wisastra R, Ghizzoni M, Maarsingh H, Minnaard AJ, Haisma HJ, Dekker FJ. Isothiazolones; thiol-reactive inhibitors of cysteine protease cathepsin B and histone acetyltransferase PCAF. Org Biomol Chem. 2011, 9(6), 1817-22.
  5. Dekker FJ, Ghizzoni M, van der Meer N, Wisastra R, Haisma HJ. Inhibition of the PCAF histone acetyl transferase and cell proliferation by isothiazolones. Bioorg Med Chem. 2009, 17(2), 460-6.
Other activities of potential interest to others

MC-member COST action biomimetic radical chemistry


Cost UE