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Chemical Ligand Space of Cereblon.

ABSTRACT: The protein cereblon serves as a substrate receptor of a ubiquitin ligase complex that can be tuned toward different target proteins by cereblon-binding agents. This approach to targeted protein degradation is exploited in different clinical settings and has sparked the development of a growing number of thalidomide derivatives. Here, we probe the chemical space of cereblon binding beyond such derivatives and work out a simple set of chemical requirements, delineating the metaclass of cereblon effectors. We report co-crystal structures for a diverse set of compounds, including commonly used pharmaceuticals, but also find that already minimalistic cereblon-binding moieties might exert teratogenic effects in zebrafish. Our results may guide the design of a post-thalidomide generation of therapeutic cereblon effectors and provide a framework for the circumvention of unintended cereblon binding by negative design for future pharmaceuticals.

SUBMITTER: Boichenko I

PROVIDER: S-EPMC6644994 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Chemical Ligand Space of Cereblon.

Boichenko Iuliia I Bär Kerstin K Deiss Silvia S Heim Christopher C Albrecht Reinhard R Lupas Andrei N AN Hernandez Alvarez Birte B Hartmann Marcus D MD

ACS omega 20180914 9

The protein cereblon serves as a substrate receptor of a ubiquitin ligase complex that can be tuned toward different target proteins by cereblon-binding agents. This approach to targeted protein degradation is exploited in different clinical settings and has sparked the development of a growing number of thalidomide derivatives. Here, we probe the chemical space of cereblon binding beyond such derivatives and work out a simple set of chemical requirements, delineating the metaclass of cereblon e ...[more]

PMID: 31459225

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