Research
Svenda and Paruch laboratories are focused on developing methods and strategies to advance fundamental research in organic chemistry and chemical biology. We use the power of modern chemical synthesis to access and explore bioactive natural products and man-made organic molecules in the context of preclinical biomedical research relevant to human medicine. Many of our projects involve collaborations with top-class biologists and an overview of the current research areas is provided below.
Highly selective inhibitors of underexplored protein kinases
Protein kinase mediated phosphor-ylation of proteins is central for activation and deactivation of numerous signaling pathways in the cell. Aberrant activity of various protein kinases is therefore frequently related to the initiation and progression of numerous diseases, in particular cancers. Correspondingly, protein kinases represent one of the most attractive class of targets for pharmacological inhibition and >70 small-molecule kinase inhibitors have been approved for clinical use. High similarity of ATP-binding sites across the whole kinase family makes identification of highly selective inhibitors a non-trivial task. While some kinases (e.g. Bcr-Abl, BTK, Akt) have been long established as attractive targets for pharmacological inhibition, others came to the forefront only recently. Significant part of our research has been focused on the discovery of new (potentially patentable) highly selective inhibitors of heretofore underexplored kinases, including CK1, CDK11, Haspin, ALK1-6, HIPK, DDR1 etc.
The series of our CK1 inhibitors forms the basis of the recently established university spin-off company CasInvent Pharma www.casinvent.com.
Selected publications:
Bactobolin class of natural antibiotics
Rapid emergence of antibacterial resistance is a gross medical concern for the future. Numerous institutions have taken on the challenge of improving the existing or developing new antibiotics for therapeutic applications.
Bactobolins are a family of complex natural products with broad-spectrum antibacterial activity against Gram-positive and Gram-negative pathogens and in vivo antiproliferative effects toward certain cancer cell lines. Bactobolins target a unique binding site at the bacterial ribosome not shared with any of the currently approved antibiotics. In 2015, Ramakrishnan lab at Cambridge UK revealed the molecular details of the bactobolin binding, opening the door to a more rational design of synthetic analogs.
Recently, we have developed a concise and flexible synthetic platform that yields novel analogs of bactobolins and supports the ongoing investigation of this underexplored family of natural antibiotics.
Selected publications:
Forskolin-inspired modulators of adenylyl cyclases
Forskolin is one of the most complex labdanes, featuring a densely substituted and highly oxygenated tricyclic scaffold. It is known for its ability to bind and allosterically stimulate membrane-bound adenylyl cyclases (ACs), central enzymes in human health responsible for converting ATP to cAMP. This unique property made forskolin a frequently used tool in biomedical research and a precursor to the semisynthetic drug colforsin.
Our lab has evaluated and advanced distinct synthetic approaches that yield fully synthetic analogs of forskolin inconceivable by the previous methods (particularly semisynthesis). Coupled with profiling of the analogs against a panel of all known isoforms of ACs, we are gaining new insights and access to forskolin-inspired molecules with varied isoform selectivity.
Selected publications:
Carbocyclic C-nucleosides
For several decades, nucleoside analogs have been of high interest to medicinal chemists. Numerous biologically active nucleosides have been identified and >30 of them are now clinically used. Classical nucleosides possess the hemiaminal motif; their chemical and metabolic stability is therefore often limited and the resulting metabolites can be a source of undesired side effects. Carbocyclic C-nucleosides have the hemiaminal motif replaced by the chemically and metabolically robust C-C-C linkage. However, these compounds are quite rare and the synthetic methodology that we reported recently, to our knowledge, represents the only sufficiently flexible synthetic route for their preparation. This technology forms the basis of your efforts focused on identification of biologically active carbocyclic C-nucleosides.
Selected publications:
Inhibitors of structure-specific nucleases
Healthy tissues rely on the DNA damage response (DDR) to protect them from DNA lesions that occur within cells on a continuous basis. Tumor cells, however, require an elevated level of DNA mutations for disease progression and switch off DDR components early in their evolution. Although this promotes cancer development, it also makes cancer cells very reliant on remaining DDR pathways to keep DNA damage below levels that cause cell death. This delicate balance makes tumor cells much more vulnerable than normal cells to inhibitors of DDR proteins. Similarly, rewiring of the DDR can cause resistance to DNA-damaging cancer therapeutics as well as targeted DDR inhibitors, such as PARP inhibitors. Structure-specific nucleases play a major role in DDR and represent a therapeutically underexplored class of targets. We identify new inhibitors of selected nucleases.
Selected publications:
- patent US 9969741 B2
- patent EP 3556756 B1
Chemistry and biology of bilirubin oxidation products
A recently initiated collaborative project aiming to advance our understanding of the underlying photochemical and biological processes occurring during phototherapy of neonatal jaundice with focus on the underexplored products of bilirubin oxidation. The pursued approach combines innovative synthetic chemistry and a battery of photochemical, chemical biology and clinical methods.
Selected publications: