Our collaborators

Current projects

Development of molecular diagnostic and therapeutic ligands for oncological targets

Cell proliferation and differentiation are often controlled by tyrosine kinase receptor pathways. These pathways are mainly regulated by GTP binding Ras proteins, which are frequently mutated in human tumours, more specifically in lung, colon or pancreatic cancer. The primary aim of the project is to develop effective covalent inhibitors against various KRAS mutants. During the last couple of years, a new regulation mechanism of Ras proteins was discovered, in which structural alterations of the active, GTP-bound Ras protein allows the Src-kinase dependent phosphorylation of the protein sidechains Y32 and Y64, thereby inactivating the Ras protein and interrupting the signalling pathway. Reactivation of the protein is possible by the dephosphorylation of the mentioned amino acids by the SHP2 tyrosine phosphatase. Preventing this reactivation might halt the proliferation of cancerous cells; therefore, our other objective is to develop SHP2 inhibitors by applying a modern fragment-based drug design approach.
Hematopoetic diseases are a large sub-group of cancer, which includes various types of leukemias that are primarily found in children. The increased response to the cytokine signal transmission is mainly caused by mutations of various tyrosine kinases (TK) or STAT3/5 transcription factors. Additionally, the hyperactive form of STAT3 and STAT5 play a critical role in non-hematopoetic malignancies, such as melanoma or prostate cancer. Due to the oncogenic behaviour of STAT3 and STAT5, a further aim of this project is to find new, small molecule inhibitors, targeting the SH2 domain of STAT5B and STAT3, with computer-aided drug discovery methods. These projects are executed with a range of collaborators in the MSCA ITN ALLODD consortium, Eötvös University, University of Veterinary Medicine Vienna and University of Toronto Mississauga.

Recent publications on this topic from The Hungarian Scientific Bibliography (MTMT)

Development of covalent probes for the identification and functional modulation of therapeutic protein targets

The use of covalent inhibition as a mechanism of action was less preferred for decades due to the potential idiosyncratic toxicity of covalent binders. However, covalent inhibitors present numerous advantages. These compounds form covalent bonds with nucleophilic sidechains of their target proteins. Based on the binding event being reversible or irreversible, covalent inhibitors exhibit large or practically infinite residence times, therefore the desired therapeutic effect can be achieved with lower dosage. Due to its relevance in chemical biology and drug discovery, we have started researching covalent inhibition in 2015. Since then, we have built a nationwide and international cooperative network, and secured funding for our activities, such as an international grant on the development of antibacterial drugs with a Slovenian partner group and a National Excellence Program grant in a consortium with the Eötvös Loránd University, on the research of novel inhibitors of the oncogenic target KRAS. In these cases, covalent inhibition can be a promising approach in terms of specificity, effectiveness and avoiding drug resistance.

Recent publications on this topic from The Hungarian Scientific Bibliography (MTMT)

Allosteric and bitopic ligands against G-protein coupled receptors

G-protein coupled receptors (GPCRs) recognise a broad spectrum of extracellular interaction partners, ranging from photons and ions to small molecules, lipids, peptides, hormones or even other proteins. Despite the therapeutic relevance of GPCRs, not many selective ligands were discovered, and the targeted polypharmacological approach meets selectivity issues, as well. This phenomenon might be the result of the high structural similarity between the orthosteric binding sites of various GPCRs subtypes. We have managed to overcome this drug design problem through intensive screening efforts, by discovering molecules that bind to allosteric or secondary binding pockets (SBPs) instead of the more conserved orthosteric sites (OBP). These molecules can inhibit or amplify the activation of GPCRs by their natural substrates. One of the main advantages of such allosteric sites is that they are less conserved, which opens the door for the design of compounds with targeted polypharmacological profiles. The exploration of the secondary binding sites of GPCRs is our primary objective in this project. We are developing “LEGO-like” molecular fragments that are recognised by the SBP of the targeted GPCR. Structure-based drug design opens the possibility to identify another set of fragments that target the OBP. Assuming that OBPs control functional activity, and SBPs control subtype specificity, merging the OBP and SBP fragments synthetically (connecting the LEGO blocks) will result in new compounds with desired subtype specificities or polypharmacological profiles. We are working together with our partners at the Indiana University and Institute of Experimental Medicine.

Recent publications on this topic from The Hungarian Scientific Bibliography (MTMT)