Discovery of a Specific CKIP-1 Ligand using DEL

Casein kinase 2-interacting protein-1 (CKIP-1) performs a critical negative role in the regulation of bone formation. Accumulated evidence strongly supports CKIP-1 as an attractive therapeutic target in osteoporosis.  As a scaffold protein lacking enzymatic activity, CKIP-1 seems to be an undruggable target, and the development of selective small molecule inhibitors targeting CKIP-1 has proven to be challenging.  One potential strategy for overcoming this hurdle is to use the technique of targeted protein degradation.

In a recent study, researchers demonstrate that VHL is a suitable E3 ligase for designing PROTAC® molecules to degrade CKIP-1 in bone marrow stem cells. The authors leverage WuXi AppTec’s DNA encoded library (DEL) to successfully identify a small molecule ligand (C77) with high affinity toward CKIP-1, underscoring the potential of using VHL and C77 to develop CKIP-1-targeted PROTACs.  This work illustrates the application of DEL technology in advancing PROTAC development for novel targets.