2. Academic Validation
  3. Leveraging Ligand Affinity and Properties: Discovery of Novel Benzamide-Type Cereblon Binders for the Design of PROTACs

Leveraging Ligand Affinity and Properties: Discovery of Novel Benzamide-Type Cereblon Binders for the Design of PROTACs

  • J Med Chem. 2023 Nov 9;66(21):14513-14543. doi: 10.1021/acs.jmedchem.3c00851.
Christian Steinebach 1,  Aleša Bricelj 2,  Arunima Murgai 3,  Izidor Sosič 2,  Luca Bischof 4,  Yuen Lam Dora Ng 3,  Christopher Heim 4,  Samuel Maiwald 4,  Matic Proj 2,  Rabea Voget 1,  Felix Feller 1,  Janez Košmrlj 5,  Valeriia Sapozhnikova 3 6 7,  Annika Schmidt 3,  Maximilian Rudolf Zuleeg 3,  Patricia Lemnitzer 3,  Philipp Mertins 6 8,  Finn K Hansen 1,  Michael Gütschow 1,  Jan Krönke 3 7,  Marcus D Hartmann 4 9
Affiliations

Affiliations

  • 1 Pharmaceutical Institute, University of Bonn, D-53121 Bonn, Germany.
  • 2 Faculty of Pharmacy, University of Ljubljana, SI-1000 Ljubljana, Slovenia.
  • 3 Department of Hematology, Oncology, and Cancer Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, D-12203 Berlin, Germany.
  • 4 Max Planck Institute for Biology Tübingen, D-72076 Tübingen, Germany.
  • 5 Faculty of Chemistry and Chemical Technology, University of Ljubljana, SI 1000 Ljubljana, Slovenia.
  • 6 Max Delbrück Center for Molecular Medicine, D-13125 Berlin, Germany.
  • 7 German Cancer Consortium (DKTK), Partner Site Berlin, DKFZ, D-69120 Heidelberg, Germany.
  • 8 Berlin Institute of Health, D-10178 Berlin, Germany.
  • 9 Interfaculty Institute of Biochemistry, University of Tübingen, D-72076 Tübingen, Germany.
PMID: 37902300 DOI: 10.1021/acs.jmedchem.3c00851
Abstract

Immunomodulatory imide drugs (IMiDs) such as thalidomide, pomalidomide, and lenalidomide are the most common Cereblon (CRBN) recruiters in proteolysis-targeting chimera (PROTAC) design. However, these CRBN ligands induce the degradation of IMiD neosubstrates and are inherently unstable, degrading hydrolytically under moderate conditions. In this work, we simultaneously optimized physiochemical properties, stability, on-target affinity, and off-target neosubstrate modulation features to develop novel nonphthalimide CRBN binders. These efforts led to the discovery of conformationally locked benzamide-type derivatives that replicate the interactions of the natural CRBN degron, exhibit enhanced chemical stability, and display a favorable selectivity profile in terms of neosubstrate recruitment. The utility of the most potent ligands was demonstrated by their transformation into potent degraders of BRD4 and HDAC6 that outperform previously described reference PROTACs. Together with their significantly decreased neomorphic ligase activity on IKZF1/3 and SALL4, these ligands provide opportunities for the design of highly selective and potent chemically inert proximity-inducing compounds.

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