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Chemical Biology group

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The Chemical Biology group combines interests in organic synthesis with its applications in medical and biological chemistry. We focus on the design, synthesis, and optimization of molecules used to study and regulate cellular processes dependent on Rab proteins and the enzyme Rab geranylgeranyltransferase (RGGT), which is responsible for regulating their activity. The group is led by prof. Katarzyna Błażewska.

WHY?
Eukaryotic cells have developed a range of specialized, membrane-bound organelles. Rab proteins play a crucial role in membrane transport and cellular homeostasis. Malfunction of Rab proteins is linked to various diseases, making them potential therapeutic targets for cancer and diabetes treatments, among others. A key requirement for Rab protein function is their post-translational modification with a lipophilic, 20-carbon geranylgeranyl chain. The enzyme RGGT is responsible for this modification.

HOW?
We are developing several strategies to regulate Rab proteins, using both classical and modern medicinal chemistry approaches:

  1. Classical RGGT Inhibitors:
    We synthesize classic RGGT enzyme inhibitors and, by studying the structure-activity relationship (SAR), determine which modifications enhance the biological effect of the inhibitor.

  2. PROTAC (PROteolysis Targeting Chimera) Compounds:
    We synthesize bifunctional PROTAC compounds that enhance inhibitory effects by incorporating an element targeting the proteasome, the cellular mechanism responsible for the degradation of unwanted proteins.

  3. Peptide Activators:
    Recognizing that not all Rab-related diseases are caused by increased activity—such as in diabetes, where some Rab proteins have reduced activity—we synthesize peptide activators for specific Rab proteins.

All of our efforts involve synthesis, while the biological effects of the synthesized compounds are studied through internal collaborations with Prof. Dr. Hab. Edyta Gendaszewska-Darmach’s team (from the Faculty of Biotechnology and Food Sciences), as well as with national and international research centers.

It’s worth noting that over the past two decades, both PROTAC compounds and peptide-based therapeutics have gained significant importance in oncology, cardiovascular, and metabolic diseases. In 2024, the first PROTAC-based drug, ARV-471, was approved by the FDA.

 

Treść (rozbudowana)
Selected papers

  1. T. Sobierajski, J. Małolepsza, M. Pichlak, E. Gendaszewska-Darmach, K. M. Błażewska, The impact of E3 ligase choice on PROTAC effectiveness in protein kinase degradation Drug Discovery Today 2024, 29, 104032. doi.org/10.1016/j.drudis.2024.104032

  2. K. F. Suazo, J. Beˇlicˇek, G. L. Schey, S. A. Auger, A. M. Petre, L. Li, K. M. Błażewska, D. Kopecˇny, M. D. Distefano Thinking outside the CaaX-box: an unusual reversible prenylation on ALDH9A1. RSC Chem. Biol. 2023, 4, 913. DOI: 10.1039/d3cb00089c.

  3. M. Pichlak, T. Sobierajski, K. M. Błażewska, E. Gendaszewska-Darmach Targeting reversible post-translational modifications with PROTACs: a focus on enzymes modifying protein lysine and arginine residues. J. Enzyme Inhibition Med. Chem. 2023, 38, 2254012; doi.org/10.1080/14756366.2023.2254012.

  4. J. Małolepsza, A. Marchwicka, R. A. Serwa, S. P. Niinivehmas, O. T. Pentikäinen, E. Gendaszewska-Darmach, K. M. Błażewska „Rational design, optimization, and biological evaluation of novel α-Phosphonopropionic acids as covalent inhibitors of Rab geranylgeranyl transferase, J. Enzyme Inhibition Med. Chem. 2022, 37, 940-951, DOI: 10.1080/14756366.2022.2053525

  5. Marchwicka,A.; Kamińska, D.; Monirialamdari, M.; Błażewska, K.M.; Gendaszewska-Darmach, E. Protein Prenyltransferases and Their Inhibitors: Structural and Functional Characterization. Int. J. Mol. Sci. 2022, 23, 5424. https://doi.org/ 10.3390/ijms23105424

  6. E. Gendaszewska-Darmach, M. Garstka, K. Błażewska “Targeting small GTPases and their prenylation in diabetes mellitus” J. Med. Chem. 2021, 64, 9677. https://doi.org/10.1021/acs.jmedchem.1c00410 7. D.

  7. Kusy, A. Marchwicka, J. Małolepsza, K. Justyna, E. Gendaszewska-Darmach, K. M. Błażewska “Synthesis of the 6-substituted imidazo[1,2-a]pyridine-3-yl-2-phosphonopropionic acids as potential inhibitors of Rab Geranylgeranyl Transferase” Front. Chem. 2021, 8, Article 596162; doi: 10.3389/fchem.2020.596162

  8. K. Justyna. J. Małolepsza, D. Kusy, W. Maniukiewicz, K. M. Błażewska “The McKenna reaction – avoiding side reactions in phosphonate deprotection” Beilstein J. Org. Chem. 2020, 16, 1436.

  9. D. Kusy, A. Wojciechowska, J. Małolepsza, K. M. Błażewska “Functionalization of imidazo[1,2-a]pyridine ring in a-phosphonoacrylates and a-phosphonopropionates via microwave-assisted Mizoroki-Heck reaction” Beilstein J. Org. Chem. 2020, 16, 15-21.

  10. D. Kusy, W. Maniukiewicz, K. M. Błażewska „Microwave -assisted synthesis of 3-formyl substituted imidazo[1,2-a]pyridines” Tetrahedron Lett. 2019, 60, No. 151244

  11. Ł. Joachimiak, K. M. Błażewska “Phosphorus-based probes as molecular tools for proteme studies: recent advances in probe development and applications” J. Med. Chem. 2018, 61, 8536.

  12. Ł. Joachimiak, A. Marchwicka, E. Gendaszewska-Darmach, K. M. Błażewska Synthesis and Biological Evaluation of Imidazole-Bearing a-Phosphonocarboxylates as Inhibitors ofRab Geranylgeranyl Transferase (RGGT) ChemMedChem 2018, 13, 842-851. 10.1002/cmdc.201700791

  13. A. Kaźmierczak, D. Kusy, S. P. Niinivehmas, J. Gmach, Ł. Joachimiak, O. T. Pentikäinen, E. Gendaszewska-Darmach, K. M. Błażewska “Identification of the privileged position in the imidazo[1,2-a]pyridine ring of phosphonocarboxylates for development of Rab geranylgeranyl transferase (RGGT) inhibitors” J. Med. Chem. 2017, 60, 8781.

  14. J. Gmach, Ł. Joachimiak, K. M. Błażewska “Aza-Michael addition of imidazole analogs” Synthesis 2016, 48, 2681.

  15. S. Sun, K. M. Błażewska, A. P. Kadina, B. A. Kashemirov, X. Duan, J. T. Triffitt, J. E. Dunford, R. G. G. Russell, F. H. Ebetino, A. J. Roelofs, F. P. Coxon, M. W. Lundy, C. E. McKenna “Fluorescent Bisphosphonate and Carboxyphosphonate Probes: A Versatile Imaging Toolkit for Applications in Bone Biology and Biomedicine” Bioconjugate Chem. 2016, 27, 329.

  16. Ł. Joachimiak, Ł. Janczewski, J. Ciekot, J. Boratyński, K. Błażewska “Applying prodrug strategy to α-phosphonocarboxylate inhibitors of Rab GGTase - synthesis and stability studies” Org. Biomol. Chem. 2015, 13, 6844.

  17. F. Coxon, Ł. Joachimiak, A. K. Najumudeen, G. Breen, J. Gmach, Ch. Oetken-Lindholm, R. Way, J. Dunford, D. Abankwa, K. M. Błażewska “Synthesis and characterization of novel phosphonocarboxylate inhibitors of RGGT“ Eur. J. Med. Chem. 2014, 84, 77-89.

  18. K. M. Błażewska „McKenna reaction – which oxygen attacks bromotrimethylsilane?” J. Org. Chem. 2014, 79, 408-412.

  19. C. E. McKenna, B. A. Kashemirov, K. M. Błażewska, I. Mallard-Favier, C. A. Stewart, J. Rojas, M. W. Lundy, F. H. Ebetino, R. A. Baron, M. C. Seabra, M. S. Marma, J. L. Bala, M. J. Rogers, F. P. Coxon, „Synthesis, Chiral HPLC Resolution and Enantiospecific Activity of a Potent New Geranylgeranyl Transferase Inhibitor, 2-Hydroxy-3-Imidazo[1,2-a]Pyridin-3-yl-2-Phosphonoproprionic Acid“, J. Med. Chem. 2010, 53, 3454-3464.

  20. A. J. Roelofs, F. P. Coxon, F. H. Ebetino, M. W. Lundy, Z. J. Henneman, G. H. Nancollas, S. Sun, K. M. Błażewska, J. L. F. Bala, B. A. Kashemirov, C. E. McKenna, M. J. Rogers “Fluorescent risedronate analogs reveal bisphosphonate uptake by bone marrow monocytes and localization around osteocytes in vivo” J. Bone Min. Res. 2010, 25, 606-616.

  21. K. Błażewska, P. Paneth, T. Gajda, “The assignment of the absolute configuration of diethyl hydroxy- and aminophosphonates by 1H and 31P NMR using naproxen as a reliable chiral derivatizing agent”, J. Org. Chem. 2007, 72, 878-887.

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