Issue 3, 2023

Accessing three-branched high-affinity cereblon ligands for molecular glue and protein degrader design

Abstract

The Petasis borono-Mannich reaction was employed for an alternative entry towards three-branched cereblon ligands. Such compounds are capabable of making multiple interactions with the protein surface and possess a suitable linker exit vector. The high-affinity ligands were used to assemble prototypic new molecular glues and proteolysis targeting chimeras (PROTACs) targeting BRD4 for degradation. Our results highlight the importance of multicomponent reactions (MCRs) in drug discovery and add new insights into the rapidly growing field of protein degraders.

Graphical abstract: Accessing three-branched high-affinity cereblon ligands for molecular glue and protein degrader design

Supplementary files

Article information

Article type
Paper
Submitted
31 10 2022
Accepted
02 1 2023
First published
03 1 2023
This article is Open Access
Creative Commons BY-NC license

RSC Chem. Biol., 2023,4, 229-234

Accessing three-branched high-affinity cereblon ligands for molecular glue and protein degrader design

R. Kuchta, C. Heim, A. Herrmann, S. Maiwald, Y. L. D. Ng, I. Sosič, T. Keuler, J. Krönke, M. Gütschow, M. D. Hartmann and C. Steinebach, RSC Chem. Biol., 2023, 4, 229 DOI: 10.1039/D2CB00223J

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