B03

© UDE/Bettina Engel-Albustin

Project Area B - Chemical Biology

Prof. Dr. Stefan Knapp

Pharmaceutical Chemistry

Goethe-University Germany, Frankfurt am Main

Phone: +49 170 3682 052
Email

Development of selective inhibitors and PROTACs for key signalling molecules regulating cell state transition and the cell cycle

Chemical tools, highly potent and selective chemical probes as well as molecules that lead to rapid and selective degradation of target proteins such as PROTACs (PROteolysis TArgeting Chimeras) are therefore versatile tools for cell based or in vivo studies on cell states that allow selective targeting of endogenous proteins in a time controlled manner. Our laboratory has a long standing interest in developing selective chemical tool compounds in particular targeting signalling molecules including protein kinases as well as modulators of epigenetic processes. One of the main contributions to this CRC will be therefore providing chemical probe collections tailored to studies on cell state transitions investigated by CRC groups and to develop new chemical probes and PROTACs for targets of high priority within this CRC. Projects that have been identified in the initial phase of this project comprise tailored probe sets for mitotic kinases and epigenetic modulators such as inhibitors of lysine methyltransferases, lysine deacetylases as well as bromodomains.

Project Members

Martin Schwalm

schwalm@pharmchem.uni-frankfurt.de

Janik Weckesser

weckesser@pharmchem.uni-frankfurt.de

Publications

    Journal articles

  • Sander, Pascal; Schwalm, Martin P.; Krämer, Andreas; Elson, Lewis; Rasch, Alexander; Masberg, Benedikt; Selig, Roland; Sievers-Engler, Adrian; Lämmerhofer, Michael; Müller, Susanne; Knapp, Stefan; Albrecht, Wolfgang; Laufer, Stefan A.
    Design, Synthesis, and Biochemical Evaluation of Novel MLK3 Inhibitors: A Target Hopping Example
    In: Journal of Medicinal Chemistry, Vol. 68, 2025, Nr. 1, pp. 674 – 694
    DOI
  • Haag, Adrian; Němec, Václav; Janovská, Pavlína; Bartošíková, Jana; Adhikari, Bikash; Müller, Juliane; Schwalm, Martin P.; Čada, Štěpán; Ohmayer, Uli; Daub, Henrik; Kim, Yeojin; Born, Florian; Wolf, Elmar; Bryja, Vítězslav; Knapp, Stefan
    Development and Discovery of a Selective Degrader of Casein Kinases 1 δ/ϵ
    In: Journal of Medicinal Chemistry, Vol. 68, 2025, Nr. 1, pp. 506 – 530
    DOI
  • Schwalm, Martin P.; Menge, Amelie; Elson, Lewis; Greco, Francesco A.; Robers, Matthew B.; Müller, Susanne; Knapp, Stefan
    Functional Characterization of Pathway Inhibitors for the Ubiquitin-Proteasome System (UPS) as Tool Compounds for CRBN and VHL-Mediated Targeted Protein Degradation
    In: ACS Chemical Biology, Vol. 20, 2025, Nr. 1, pp. 94 – 104
    DOI (Open Access)
  • Schwalm, Martin P.; Knapp, Stefan
    Single-plate kinome screening in live-cells to enable highly cost-efficient kinase inhibitor profiling
    In: SLAS Discovery, Vol. 31, 2025, 100214
    DOI (Open Access)
  • Miletić, Nebojša; Weckesser, Janik; Mosler, Thorsten; Rathore, Rajeshwari; Hoffmann, Marina E.; Gehrtz, Paul; Schlesiger, Sarah; Hartung, Ingo V.; Berner, Nicola; Wilhelm, Stephanie; Müller, Juliane; Adhikari, Bikash; Němec, Václav; Sivashanmugam, Saran Aswathaman; Elson, Lewis; Holzmann, Hanna; Schwalm, Martin P.; Hoffmann, Lasse; Abdul Azeez, Kamal Rayees; Müller, Susanne; Kuster, Bernhard; Wolf, Elmar; Đikić, Ivan; Knapp, Stefan
    Workflow for E3 Ligase Ligand Validation for PROTAC Development
    In: ACS Chemical Biology, Vol. 20, 2025, Nr. 2, pp. 507 – 521
    DOI (Open Access)
  • Owens, Dominic D. G.; Maitland, Matthew E. R.; Khalili Yazdi, Aliakbar; Song, Xiaosheng; Reber, Viviane; Schwalm, Martin P.; Machado, Raquel A. C.; Bauer, Nicolas; Wang, Xu; Szewczyk, Magdalena M.; Dong, Cheng; Dong, Aiping; Loppnau, Peter; Calabrese, Matthew F.; Dowling, Matthew S.; Lee, Jisun; Montgomery, Justin I.; O’Connell, Thomas N.; Subramanyam, Chakrapani; Wang, Feng; Adamson, Ella C.; Schapira, Matthieu; Gstaiger, Matthias; Knapp, Stefan; Vedadi, Masoud; Min, Jinrong; Lajoie, Gilles A.; Barsyte-Lovejoy, Dalia; Owen, Dafydd R.; Schild-Poulter, Caroline; Arrowsmith, Cheryl H.
    A chemical probe to modulate human GID4 Pro/N-degron interactions
    In: Nature Chemical Biology, Vol. 20, 2024, Nr. 9, pp. 1164 – 1175
    DOI
  • Schwalm, Martin P.; Dopfer, Johannes; Kumar, Adarsh; Greco, Francesco A.; Bauer, Nicolas; Löhr, Frank; Heering, Jan; Cano-Franco, Sara; Lechner, Severin; Hanke, Thomas; Jaser, Ivana; Morasch, Viktoria; Lenz, Christopher; Fearon, Daren; Marples, Peter G.; Tomlinson, Charles W. E.; Brunello, Lorene; Saxena, Krishna; Adams, Nathan B. P.; von Delft, Frank; Müller, Susanne; Stolz, Alexandra; Proschak, Ewgenij; Kuster, Bernhard; Knapp, Stefan; Rogov, Vladimir V.
    Critical assessment of LC3/GABARAP ligands used for degrader development and ligandability of LC3/GABARAP binding pockets
    In: Nature Communications, Vol. 15, 2024, Nr. 1, 10204
    DOI (Open Access)
  • Schwarz, Moritz; Kurkunov, Maksym; Wittlinger, Florian; Rudalska, Ramona; Wang, Guiqun; Schwalm, Martin Peter; Rasch, Alexander; Wagner, Benedikt; Laufer, Stefan A.; Knapp, Stefan; Dauch, Daniel; Gehringer, Matthias
    Development of Highly Potent and Selective Covalent FGFR4 Inhibitors Based on SNAr Electrophiles
    In: Journal of Medicinal Chemistry, Vol. 67, 2024, Nr. 8, pp. 6549 – 6569
    DOI
  • Shah Zaib Saleem, Rahman; Schwalm, Martin P.; Knapp, Stefan
    Expanding the ligand spaces for E3 ligases for the design of protein degraders
    In: Bioorganic and Medicinal Chemistry, Vol. 105, 2024, 117718
    DOI (Open Access)
  • Schwalm, Martin P.; Saxena, Krishna; Müller, Susanne; Knapp, Stefan
    Luciferase- and HaloTag-based reporter assays to measure small-molecule-induced degradation pathway in living cells
    In: Nature Protocols, Vol. 19, 2024, Nr. 8, pp. 2317 – 2357
    DOI
  • Gybeľ, Tomáš; Čada, Štěpán; Klementová, Darja; Schwalm, Martin P.; Berger, Benedict-Tilman; Šebesta, Marek; Knapp, Stefan; Bryja, Vítězslav
    Splice variants of CK1α and CK1α-like : Comparative analysis of subcellular localization, kinase activity, and function in the Wnt signaling pathway
    In: The Journal of Biological Chemistry (JBC), Vol. 300, 2024, Nr. 7, 107407
    DOI (Open Access)
  • Schwalm, Martin P.; Knapp, Stefan; Rogov, Vladimir V.
    Toward effective Atg8-based ATTECs : Approaches and perspectives
    In: Journal of Cellular Biochemistry, Vol. 125, 2024, Nr. 11: Special Issue: New Horizons in Selective Autophagy, e30380
    DOI (Open Access)
  • Dopfer, Johannes; Vasta, James D.; Müller, Susanne; Knapp, Stefan; Robers, Matthew B.; Schwalm, Martin P.
    tracerDB : a crowdsourced fluorescent tracer database for target engagement analysis
    In: Nature Communications, Vol. 15, 2024, Nr. 1, 5646
    DOI (Open Access)
  • Schwalm, Martin P.; Krämer, Andreas; Dölle, Anja; Weckesser, Janik; Yu, Xufen; Jin, Jian; Saxena, Krishna; Knapp, Stefan
    Tracking the PROTAC degradation pathway in living cells highlights the importance of ternary complex measurement for PROTAC optimization
    In: Cell Chemical Biology, Vol. 30, 2023, Nr. 7, pp. 753 – 765.e8
    DOI, Online Full Text (Open Access)
  • Schwalm, Martin P.; Berger, Lena M.; Meuter, Maximilian N.; Vasta, James D.; Corona, Cesear R.; Röhm, Sandra; Berger, Benedict-Tilman; Farges, Frederic; Beinert, Sebastian M.; Preuss, Franziska; Morasch, Viktoria; Rogov, Vladimir V.; Mathea, Sebastian; Saxena, Krishna; Robers, Matthew B.; Müller, Susanne; Knapp, Stefan
    A Toolbox for the Generation of Chemical Probes for Baculovirus IAP Repeat Containing Proteins
    In: Frontiers in Cell and Developmental Biology, Vol. 10, 2022, 886537
    DOI (Open Access)
  • Schwalm, Martin P.; Knapp, Stefan
    BET bromodomain inhibitors
    In: Current Opinion in Chemical Biology, Vol. 68, 2022, 102148
    DOI
  • Bozilovic, Jelena; Eing, Lorenz; Berger, Benedict-Tilman; Adhikari, Bikash; Weckesser, Janik; Berner, Nicola B.; Wilhelm, Stephanie; Kuster, Bernhard; Wolf, Elmar; Knapp, Stefan
    Novel, highly potent PROTACs targeting AURORA-A kinase
    In: Current Research in Chemical Biology, Vol. 2, 2022, 100032
    DOI (Open Access)
  • Němec, Václav; Schwalm, Martin P.; Müller, Susanne; Knapp, Stefan
    PROTAC degraders as chemical probes for studying target biology and target validation
    In: Chemical Society Reviews, Vol. 51, 2022, Nr. 18, pp. 7971 – 7993
    DOI

    • Preprints

  • Klink, Nikolas; Urban, Sebastian; Seier, Johanna A.; Adhikari, Bikash; Schwalm, Martin P.; Müller, Juliane; Dorsch, Madeleine; Kaschani, Farnusch; Koch, Johannes; Führer, Siska; Kaiser, Markus; Schulze, Nina; Knapp, Stefan; Wolf, Elmar; Paschen, Annette; Grüner, Barbara M.; Gersch, Malte
    Targeted degradation of USP7 in solid cancer cells reveals disparate effects of deubiquitinase inhibition vs. acute protein depletion
    2025
    DOI, Online Full Text (Open Access)
  • Scholes, Natalie S.; Bertoni, Martino; Comajuncosa-Creus, Arnau; Kladnik, Katharina; Frommelt, Fabian; Hinterndorfer, Matthias; Razumkov, Hlib; Prokofeva, Polina; Schwalm, Martin P.; Imrichova, Hana; Barone, Eleonora; Schätz, Caroline; Rukavina, Andrea; Koren, Anna; Kubicek, Stefan; Knapp, Stefan; Gray, Nathanael S.; Superti-Furga, Giulio; Kuster, Bernhard; Aloy, Patrick; Winter, Georg E.
    Inhibitor-induced supercharging of kinase turnover via endogenous proteolytic circuits
    2024
    DOI (Open Access)

    • Book articles / Proceedings papers

  • Schwalm, Martin P.; Dopfer, Johannes; Knapp, Stefan; Rogov, Vladimir V.
    High-Throughput Screening for LC3/GABARAP Binders Utilizing the Fluorescence Polarization Assay
    In: Selective Autophagy: Methods and Protocols / Nezis, Ioannis P. (Eds.). New York: Humana Press Inc., 2024, pp. 203 – 218
    DOI
  • Schwalm, Martin P.; Babaahmadi, Atoosa Karimi; Ackloo, Suzanne; Knapp, Stefan
    Targeting the Acetylation Reader Family : Bromodomain Proteins
    In: Epigenetic Drug Discovery / Chan, Ho Man; Arrowsmith, Cheryl (Eds.). London: Royal Society of Chemistry, 2024, pp. 404 – 439
    DOI
  • Dopfer, Johannes; Schwalm, Martin P.; Knapp, Stefan; Rogov, Vladimir V.
    Thermodynamic Characterization of LC3/GABARAP : Ligand Interactions by Isothermal Titration Calorimetry
    In: Selective Autophagy / Nezis, Ioannis P. (Eds.). Totowa, NJ: Humana Press Inc., 2024, pp. 219 – 235
    DOI

« Project B02  Project B04 »