Feedback

Development of heterobifunctional degraders for RNA and RNA-modifying enzymes

Affiliation
Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudingerweg 5, 55128 Mainz, Germany
Weldert, Annabelle C.;
Affiliation
Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudingerweg 5, 55128 Mainz, Germany
Frey, Ariane;
Affiliation
Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudingerweg 5, 55128 Mainz, Germany
Zimmer, Collin;
Affiliation
Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudingerweg 5, 55128 Mainz, Germany
Rodriguez, Laura Almena;
Affiliation
Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudingerweg 5, 55128 Mainz, Germany
Krähe, Franziska;
Affiliation
Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudingerweg 5, 55128 Mainz, Germany
Kersten, Christian;
Affiliation
Department of Molecular, Cellular, and Developmental Biology, Yale University, 219 Prospect Street, CT 06520 8103 New Haven, USA.
Crews, Craig M.;
Affiliation
Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudingerweg 5, 55128 Mainz, Germany
Schirmeister, Tanja;
Affiliation
Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudingerweg 5, 55128 Mainz, Germany
Barthels, Fabian

Proteolysis targeting chimeras (PROTACs) are novel therapeutic modalities that have emerged in recent years. These heterobifunctional compounds recruit E3 ligases, such as cereblon (CRBN) or Von Hippel Lindau factor (VHL), in close proximity to a protein of interest (POI), leading to targeted degradation of the POI. Since 2019 several PROTACs have entered clinical trials, mainly targeting proteins involved in different types of cancer and autoimmune diseases. We designed and synthesized PROTACs targeting the human METTL3/14 methyltransferase. METTL3/14 is involved in multifaceted biological activities, such as cell cycle, apoptosis, autophagy and differentiation, and has an impact on numerous types of cancers including breast
cancer, lung cancer, and acute myeloid leukemia. Additionally we are interested in, ribonuclease-targeting chimeras (RIBOTACs). Similar to PROTACs, RIBOTACs function as targeted degraders, however targeting an RNA of interest (ROI) instead of a POI. RIBOTACs can selectively bind and degrade ROIs by activation of RNase L, part of the innate immune system, an otherwise latent ribonuclease. Choosing the optimal composition of heterobifunctional molecules includes deciding on optimal linker length, type of recruiter, and type of POI/ROI binder. Therefore it is important to characterize the interaction between our molecules and their respective interaction partner. Hence, we employed various biophysical methods such as fluorescence polarization (FP) and Förster resonance energy transfer (FRET) based assays.
Moreover, characterization of the ternary complex es is essential for successful degrader development. To achieve this, we developed a homogeneous time resolved fluorescence (HTRF) based method in our PROTAC studies.  Additionally, we investigated the permeability of our compounds.

Cite

Citation style:
Could not load citation form.

Access Statistic

Total:
Downloads:
Abtractviews:
Last 12 Month:
Downloads:
Abtractviews:

Rights

Use and reproduction: