TY - DATA T1 - Chemical Ligand Space of Cereblon PY - 2018/09/14 AU - Iuliia Boichenko AU - Kerstin Bär AU - Silvia Deiss AU - Christopher Heim AU - Reinhard Albrecht AU - Andrei N. Lupas AU - Birte Hernandez Alvarez AU - Marcus D. Hartmann UR - https://acs.figshare.com/articles/journal_contribution/Chemical_Ligand_Space_of_Cereblon/7088720 DO - 10.1021/acsomega.8b00959.s001 L4 - https://ndownloader.figshare.com/files/13034744 KW - cereblon effectors KW - protein KW - chemical Ligand Space KW - pharmaceutical KW - derivative KW - cereblon binding KW - minimalistic cereblon-binding moieties KW - report co-crystal structures N2 - 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. ER -