Identifying Small Molecules that Bind to the Cbl-b E3-Ligase

The Casitas B-lineage E3 ligases are a family of closely related RING-type, mono-subunit E3 ligases (c-Cbl, Cbl-b, Cbl3) which play important roles in the regulation of tyrosine kinases. Cbl-b has attracted particular interest as it has been shown to be a key check-point regulator of both the innate and adaptive immune system and mice lacking Cblb have demonstrated enhanced T-cell killing and spontaneous rejection of tumours. Small molecules that bind to Cblb may therefore act as novel immune checkpoint regulators. Furthermore, as Cbl-b is an E3 ligase they could also serve as the basis for generating novel, alternative PROTACs.