De-Novo Design of Cereblon (CRBN) Effectors Guided by Natural Hydrolysis 
Products of Thalidomide Derivatives

Heim, C; Pliatsika, D; Mousavizadeh, F; Bär, K; Hernandez Alvarez, B; Giannis, A; Hartmann, MD

doi:10.1021/acs.jmedchem.9b00454

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De-Novo Design of Cereblon (CRBN) Effectors Guided by Natural Hydrolysis Products of Thalidomide Derivatives

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Heim, C
Department Protein Evolution, Max Planck Institute for Developmental Biology, Max Planck Society;
Molecular Recognition and Catalysis Group, Department Protein Evolution, Max Planck Institute for Developmental Biology, Max Planck Society;

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Bär, K
Department Protein Evolution, Max Planck Institute for Developmental Biology, Max Planck Society;

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Hernandez Alvarez, B
Department Protein Evolution, Max Planck Institute for Developmental Biology, Max Planck Society;
Conservation of Protein Structure and Function Group, Department Protein Evolution, Max Planck Institute for Developmental Biology, Max Planck Society;

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Hartmann, MD
Department Protein Evolution, Max Planck Institute for Developmental Biology, Max Planck Society;
Molecular Recognition and Catalysis Group, Department Protein Evolution, Max Planck Institute for Developmental Biology, Max Planck Society;

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引用

Heim, C., Pliatsika, D., Mousavizadeh, F., Bär, K., Hernandez Alvarez, B., Giannis, A., & Hartmann, M. (2019). De-Novo Design of Cereblon (CRBN) Effectors Guided by Natural Hydrolysis Products of Thalidomide Derivatives. Journal of Medicinal Chemistry, 62(14), 6615-6629. doi:10.1021/acs.jmedchem.9b00454.

引用: https://hdl.handle.net/21.11116/0000-000A-686F-6

要旨

Targeted protein degradation via cereblon (CRBN), a substrate receptor of an E3 ubiquitin ligase complex, is an increasingly important strategy in various clinical settings, in which the substrate specificity of CRBN is altered via the binding of small-molecule effectors. To date, such effectors are derived from thalidomide and confer a broad substrate spectrum that is far from being fully characterized. Here, we employed a rational and modular approach to design novel and minimalistic CRBN effectors. In this approach, we took advantage of the binding modes of hydrolyzed metabolites of several thalidomide-derived effectors, which we elucidated via crystallography. These yielded key insights for the optimization of the minimal core binding moiety and its linkage to a chemical moiety that imparts substrate specificity. Based on this scaffold, we present a first active de-novo CRBN effector that is able to degrade the neo-substrate IKZF3 in the cell culture.