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

• Published in: Journal of medicinal chemistry Vol. 66; no. 21; pp. 14513 - 14543
• Main Authors: Steinebach, Christian, Bricelj, Aleša, Murgai, Arunima, Sosič, Izidor, Bischof, Luca, Ng, Yuen Lam Dora, Heim, Christopher, Maiwald, Samuel, Proj, Matic, Voget, Rabea, Feller, Felix, Košmrlj, Janez, Sapozhnikova, Valeriia, Schmidt, Annika, Zuleeg, Maximilian Rudolf, Lemnitzer, Patricia, Mertins, Philipp, Hansen, Finn K., Gütschow, Michael, Krönke, Jan, Hartmann, Marcus D.
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 09.11.2023; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; MULTIPLE-MYELOMA; ANTIANGIOGENIC PROPERTIES; RECOGNITION; IMMOBILIZED ARTIFICIAL MEMBRANE; LENALIDOMIDE; DEGRADATION; FLUORINE; BROMODOMAIN; BINDING; HYDROGEN-BONDS
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.3c00851

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.