2. Academic Validation
  3. Click. Screen. Degrade. A Miniaturized D2B Workflow for Rapid PROTAC Discovery

Click. Screen. Degrade. A Miniaturized D2B Workflow for Rapid PROTAC Discovery

  • J Med Chem. 2026 Feb 12;69(3):2599-2624. doi: 10.1021/acs.jmedchem.5c02543.
Marko Mitrović 1 2,  Francesco Aleksy Greco 1 2 3,  Yiliam Cruz García 4,  Aleksandar Lučić 1 2,  Lasse Hoffmann 1 2,  Rohit Chander 1,  Julia Schönfeld 1,  Nick Liebisch 1,  Saran Aswathaman Sivashanmugam 1 2,  Martin Peter Schwalm 1 2 3,  Markus Egner 5,  Max Lewandowski 5,  Daniel Merk 5,  Viktoria Morasch 1 2,  Elmar Wolf 4,  Susanne Müller 1 2,  Thomas Hanke 1 2,  Ewgenij Proschak 1 6,  Kerstin Hiesinger 1,  Stefan Knapp 1 2 3
Affiliations

Affiliations

  • 1 Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, Frankfurt am Main 60438, Germany.
  • 2 Structural Genomics Consortium (SGC), Buchmann Institute for Molecular Life Sciences (BMLS), Max-von-Laue-Str. 15, Frankfurt am Main 60438, Germany.
  • 3 German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
  • 4 Institute of Biochemistry, University of Kiel, Rudolf-Höber-Str. 1, Kiel 24118, Germany.
  • 5 Department of Pharmacy, Ludwig-Maximilians-Universität (LMU) München, Munich 81377, Germany.
  • 6 Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), Theodor-Stern-Kai 7, Frankfurt am Main 60596, Germany.
PMID: 41575171 DOI: 10.1021/acs.jmedchem.5c02543
Abstract

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.

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