Influence of Linker Attachment Points on the Stability and Neosubstrate Degradation of Cereblon Ligands

Aleša Bricelj; Yuen Lam Dora Ng; Dominic Ferber; Robert Kuchta; Sina Müller; Marius Monschke; Karl G Wagner; Jan Krönke; Izidor Sosič; Michael Gütschow; Christian Steinebach

doi:10.1021/acsmedchemlett.1c00368

Influence of Linker Attachment Points on the Stability and Neosubstrate Degradation of Cereblon Ligands

ACS Med Chem Lett. 2021 Oct 18;12(11):1733-1738. doi: 10.1021/acsmedchemlett.1c00368. eCollection 2021 Nov 11.

Affiliations

¹ Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia.
² Department of Internal Medicine with Focus on Hematology, Oncology and Tumor Immunology, Charité, Hindenburgdamm 30, 12203 Berlin, Germany.
³ Pharmaceutical Institute, Department of Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
⁴ Pharmaceutical Institute, Pharmaceutical Technology, University of Bonn, Gerhard-Domagk-Straße 3, 53121 Bonn, Germany.

Abstract

Proteolysis targeting chimeras (PROTACs) hijacking the cereblon (CRBN) E3 ubiquitin ligase have emerged as a novel paradigm in drug development. Herein we found that linker attachment points of CRBN ligands highly affect their aqueous stability and neosubstrate degradation features. This work provides a blueprint for the assembly of future heterodimeric CRBN-based degraders with tailored properties.