Drug Design and Medicinal Chemistry

About our group

We have conducted extensive research on inhibitors of methyltransferases—enzymes that play crucial roles in epigenetic regulation and viral replication. By designing and synthesizing novel methyltransferase inhibitors, we have advanced the understanding of these enzymes and opened potential therapeutic avenues for diseases where methyltransferases are implicated, such as cancer and viral infections.

Our exploration of inhibitors of kinases, important regulators of cellular processes, has led to the design of selective kinase inhibitors with implications for treating diseases related to kinase dysregulation, including certain cancers and inflammatory conditions.
Significant advances have been made in the development of STING (Stimulator of Interferon Genes) agonists. STING plays a critical role in the innate immune response to pathogens and cancer cells. By designing novel STING agonists, we have contributed to potential new therapies in cancer immunotherapy and antiviral treatments.

Our group has discovered a novel class of powerful agonists of CAR - constitutive androstane receptor. CAR plays a vital role in the management of bile acid as well as lipid and glucose metabolism. These molecules might be used to treat cholestasis or to treat metabolic disorders such as obesity, fatty liver disease, and type 2 diabetes. A spinoff company, Lipidera, is devoted to further developing this discovery into clinical trials.

We have developed new chemical probes and methodologies to study biological systems. These tools have been instrumental in elucidating complex biological pathways and have applications in both basic research and drug development.

We have secured a number of patents for novel compounds and innovative therapeutic approaches. We actively collaborate with renowned international researchers and systematically publish our research results in reputable scientific journals.

Discovery and structural characterization of monkeypox virus methyltransferase VP39 inhibitors reveal similarities to SARS-CoV-2 nsp14 methyltransferase

J. Šilhán M. Klíma T. Otava P. Škvára D. Chalupská K. Chalupský J. Kozic R. Nencka E. Bouřa

Nature Communications 14: 2259 (2023)

Monkeypox is a disease with pandemic potential. It is caused by the monkeypox virus (MPXV), a double-stranded DNA virus from the Poxviridae family, that replicates in the cytoplasm and must encode for its own RNA processing machinery including the capping machinery. Here, we present crystal structures of its 2′-O-RNA methyltransferase (MTase) VP39 in complex with the pan-MTase inhibitor sinefungin and a series of inhibitors that were discovered based on it. A comparison of this 2′-O-RNA MTase with enzymes from unrelated single-stranded RNA viruses (SARS-CoV-2 and Zika) reveals a conserved sinefungin binding mode, implicating that a single inhibitor could be used against unrelated viral families. Indeed, several of our inhibitors such as TO507 also inhibit the coronaviral nsp14 MTase.

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Discovery of Novel Human Constitutive Androstane Receptor Agonists with the Imidazo[1,2-a]pyridine Structure

I. Mejdrová J. Dušek K. Škach A. Štefela J. Škoda K. Chalupský K. Dohnalová I. Pávková T. Kronenberger A. Rashidian L. Smutná V. Duchoslav T. Smutný P. Pávek R. Nencka

Journal of Medicinal Chemistry 66 (4): 2422–2456 (2023)

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Inhibition of FLT3-ITD Kinase in Acute Myeloid Leukemia by New Imidazo[1,2-b]pyridazine Derivatives Identified by Scaffold Hopping

P. Břehová E. Řezníčková K. Škach R. Jorda M. Dejmek V. Vojáčková M. Šála M. Kovalová M. Dračínský A. Dolníková T. Strmeň M. Kinnertová K. Chalupský A. Dvořáková T. Gucký H. Mertlíková Kaiserová P. Klener R. Nencka V. Kryštof

Journal of Medicinal Chemistry 66 (16): 11133–11157 (2023)

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Vinylphosphonate-based cyclic dinucleotides enhance STING-mediated cancer immunotherapy