Invited Speaker Oral Presentation Inaugural Australian Ubiquitin Summit 2025

Targeting new E3 Ligases and validating them for PROTAC development (130753)

Stefan Knapp 1
  1. Goethe-Universität Frankfurt, Frankfurt Am Main, HESSEN, Germany

The human E3 ligase family is a large and diverse family of proteins that has not been widely explored for the development of ligands and PROTACs (PROtein Targeting Chimeras). In this talk I will discuss strategies for the identification of new ligands using DEL-ML (DNA-encoded library screening coupled to machine learning) and high throughput crystallographic fragment screening as well as strategies for the validation of E3 ligands for the development of the next generation of PROTAC degraders. I will also discuss a streamlined PROTAC synthesis platform using click chemistry in conjunction with a “direct-to-biology” screening approach.

  1. Crystallographic fragment screening reveals ligand hotspots in TRIM21 PRY-SPRY domain. Kim Y, Lučić A, Lenz C, Farges F, Schwalm MP, Saxena K, Hanke T, Marples PG, Aschenbrenner JC, Fearon D, von Delft F, Krämer A, Knapp S. Commun Chem. 2025 Jun 13;8(1):185. doi: 10.1038/s42004-025-01574-3.
  2. Workflow for E3 Ligase Ligand Validation for PROTAC Development. Miletić N, Weckesser J, Mosler T, Rathore R, Hoffmann ME, Gehrtz P, Schlesiger S, Hartung IV, Berner N, Wilhelm S, Müller J, Adhikari B, Němec V, Sivashanmugam SA, Elson L, Holzmann H, Schwalm MP, Hoffmann L, Abdul Azeez KR, Müller S, Kuster B, Wolf E, Đikić I, Knapp S. ACS Chem Biol. 2025 Feb 21;20(2):507-521. doi: 10.1021/acschembio.4c00812.
  3. PROTAC-mediated degradation reveals a non-catalytic function of AURORA-A kinase. Adhikari B, Bozilovic J, Diebold M, Schwarz JD, Hofstetter J, Schröder M, Wanior M, Narain A, Vogt M, Dudvarski Stankovic N, Baluapuri A, Schönemann L, Eing L, Bhandare P, Kuster B, Schlosser A, Heinzlmeir S, Sotriffer C, Knapp S, Wolf E. Nat Chem Biol. 2020 Nov;16(11):1179-1188. doi: 10.1038/s41589-020-00652-y.
  4. Functional Characterization of Pathway Inhibitors for the Ubiquitin-Proteasome System (UPS) as Tool Compounds for CRBN and VHL-Mediated Targeted Protein Degradation. Schwalm MP, Menge A, Elson L, Greco FA, Robers MB, Müller S, Knapp S. ACS Chem Biol. 2025 Jan 17;20(1):94-104. doi: 10.1021/acschembio.4c00450.