%0 Journal Article
%A Mitrović, Marko
%A Greco, Francesco Aleksy
%A García, Yiliam Cruz
%A Lučić, Aleksandar
%A Hoffmann, Lasse
%A Chander, Rohit
%A Schönfeld, Julia
%A Liebisch, Nick
%A Sivashanmugam, Saran Aswathaman
%A Schwalm, Martin Peter
%A Egner, Markus
%A Lewandowski, Max
%A Merk, Daniel
%A Morasch, Viktoria
%A Wolf, Elmar
%A Müller, Susanne
%A Hanke, Thomas
%A Proschak, Ewgenij
%A Hiesinger, Kerstin
%A Knapp, Stefan
%T Click. Screen. Degrade. A Miniaturized D2B Workflow for Rapid PROTAC Discovery.
%J Journal of medicinal chemistry
%V nn
%@ 0095-9065
%C Washington, DC
%I ACS
%M DKFZ-2026-00198
%P nn
%D 2026
%Z epub
%X Targeted protein degradation is one of the fastest developing fields in medicinal chemistry and chemical biology. Despite significant development in assay technologies and inhibitor discovery, the development of PROTACs remains a challenging endeavor since rational design approaches remain widely elusive. Our workflow eliminates the rate-limiting step of classic synthesis, namely compound purification, and pairs it with high-throughput, semi-automated plate-based synthesis, and direct cellular assay evaluation. We applied this direct-to-biology approach to four diverse targets, demonstrating the general applicability of this technology. PROTAC synthesis was realized by using the highly efficient copper-catalyzed azide-alkyne cycloaddition reaction. This simplified reaction setup enabled synthesis in the nanomole scale with reaction volumes as low as 5 μL. The high-throughput strategy allows hundreds of PROTACs to be synthesized and evaluated within a few days, facilitating comprehensive assessment of target degradability, rapid hit identification, and selection of the most suitable E3 ligase for degrader development.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:41575171
%R 10.1021/acs.jmedchem.5c02543
%U https://inrepo02.dkfz.de/record/308665