Novel DEL Hit That Binds in the Cbl-b SH2 Domain

Casitas B lymphoma-b (Cbl-b), a RING finger E3 ubiquitin ligase, is a key regulator of T cell activation and plays an important role in immune responses against tumors.  Cbl-b has been identified as an attractive target for cancer immunotherapy due to its role in promoting an immunosuppressive tumor environment.

WuXi AppTec contributed to a study which identified a hit compound following screening of a DNA-encoded library (DEL) using activated Cbl-b. The authors employed a structure-based approach to optimize this hit, resulting in a compound with measurable cell activity. This work highlights the potential of small molecule inhibitors that can bind to SH2 domains and block protein-protein interactions.