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. 2019 May 28;10(6):1037-1041.
doi: 10.1039/c9md00185a. eCollection 2019 Jun 1.

A MedChem toolbox for cereblon-directed PROTACs

Christian Steinebach  1 , Izidor Sosič  2 , Stefanie Lindner  3 , Aleša Bricelj  2 , Franziska Kohl  1 , Yuen Lam Dora Ng  3 , Marius Monschke  4 , Karl G Wagner  4 , Jan Krönke  3 , Michael Gütschow  1
Affiliations

A MedChem toolbox for cereblon-directed PROTACs

Christian Steinebach et al. Medchemcomm. .

Abstract

A modular chemistry toolbox was developed for cereblon-directed PROTACs. A variety of linkers was attached to a CRBN ligand via the 4-amino position of pomalidomide. We used linkers of different constitution to modulate physicochemical properties. We equipped one terminus of the linker with a set of functional groups, e.g. protected amines, protected carboxylic acids, alkynes, chloroalkanes, and protected alcohols, all of which are considered to be attractive for PROTAC design. We also highlight different opportunities for the expansion of the medicinal chemists' PROTAC toolbox towards heterobifunctional molecules, e.g. with biotin, fluorescent, hydrophobic and peptide tags.

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Figures

Fig. 1
Fig. 1. PROTAC-induced degradation of target proteins.
Fig. 2
Fig. 2. Examples of bifunctional CRBN-directed PROTACs.
Fig. 3
Fig. 3. Toolbox compounds 1–5 with different linkers and various functional groups (FG).
Fig. 4
Fig. 4. CRBN-addressing probes 6 and 7 with a biotin and fluorescent tag.
Fig. 5
Fig. 5. Hydrophobically tagged CRBN ligands 8.
Fig. 6
Fig. 6. Hydrophobically tagged CRBN ligands 8 induce degradation of IKZF1, but not of CRBN. MM1S cells were treated for 16 h at the indicated concentrations (μM). For comparison, pomalidomide (POM), the CRBN homo-PROTAC 15a and the CRBN-VHL hetero-PROTAC CRBN-6-5-5-VHL were used. The quantification was performed with IKZF1 levels normalized to tubulin, then to DMSO control (100%).
Fig. 7
Fig. 7. CRBN ligand coupled to a linker (2d) and to a cell-penetrating peptide (9).
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