Publications
2025
Biology and pharmacological inhibition of homeodomain-interacting protein kinases (HIPKs). Štefek, A.; Paruch, K.*
Front. Chem. Biol. 2025, 4, doi: 10.3389/fchbi.2025.1441138.
Homeodomain-interacting protein kinases (HIPKs) represent a relatively underexplored sub-family of serine/threonine protein kinases. However, the recently published studies point to the role of HIPKs in the developmental biology and etiology of pathological states, in particular cancer, and potential therapeutic applications of targeting this kinase family. This review summarizes the biology of HIPKs and their heretofore published small-molecule inhibitors.
Discovery of new inhibitors of nuclease MRE11. Nikulenkov, F.; Carbain, B.; Biswas, R.; Havel, S.; Prochazkova, J.; Sisakova, A.; Chavdarova, M.; Marini, V.; Vsiansky, V.; Weisova, V.; Slavikova, K.; Biradar, D.; Khirsariya, P.; Vitek, M.; Sedlak, D.; Bartunek, P.; Daniel, L.; Brezovsky, J.; Damborsky, J.; Paruch, K.*; Krejci, L.*
Eur. J. Med. Chem. 2025, accepted.
MRE11 nuclease is a central player in signaling and processing DNA damage, and in resolving stalled replication forks. Here, we describe the identification and characterization of new MRE11 inhibitors MU147 and MU1409. Both compounds inhibit MRE11 nuclease more specifically and effectively than the relatively weak state-of-the-art inhibitor mirin. They also abrogate double-strand break repair mechanisms that rely on MRE11 nuclease activity, without impairing ATM activation. Inhibition of MRE11 also impairs nascent strand degradation of stalled replication forks and selectively affects BRCA2-deficient cells. Herein, we illustrate that our newly discovered compounds MU147 and MU1409 can be used as chemical probes to further explore the biological role of MRE11 and support the potential clinical relevance of pharmacological inhibition of this nuclease.
Development of a cell-permeable Biotin-HaloTag ligand to explore functional differences between protein variants across cellular generations. Yadav, A. K.; Jadhav, A. S.; Szczepanik, P. M.; Fagherazzi, P.; Kabelka, I.; Vácha, R.; Svenda, J.*; Polasek-Sedlackova, H.*
bioRxiv, doi: 10.1101/2024.09.18.613519