Chelsi M. Almodóvar‐Rivera, Zhen Zhang, Jingyao Li, Haibo Xie, Yu Zhao, Le Guo, Marissa G. Mannhardt, Weiping Tang

A Modular Chemistry Platform for the Development of a Cereblon E3 Ligase‐Based Partial PROTAC Library

  • Organic Chemistry
  • Molecular Biology
  • Molecular Medicine
  • Biochemistry
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AbstractProteolysis targeting chimeras (PROTACs) are a promising therapeutic strategy to selectively promote the degradation of protein targets by exploiting the ubiquitin‐proteasome system. Among the limited number of E3 ligase ligands discovered for the PROTAC technology, ligands of cereblon (CRBN) E3 ligase, such as pomalidomide, thalidomide, or lenalidomide, are the most frequently used for the development of PROTACs. Our group previously reported that a phenyl group could be tolerated on the C4‐position of lenalidomide as the ligand of CRBN to develop PROTACs. Herein, we report a modular chemistry platform for the efficient attachment of various ortho‐, meta‐, and para‐substituted phenyls to the C4‐position of the lenalidomide via Suzuki cross‐coupling reaction, which allows the systematic investigation of the linker effect for the development of PROTACs against any target. We examined the substrate scope by preparing twelve lenalidomide‐derived CRBN E3 ligase ligands with different linkers.

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