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

Casitas B系E3连接酶是一类关系密切的环型单亚单位E3连接酶家族(c-Cb1、Cb1-b、Cbl3)，在酪氨酸激酶的调节中发挥重要作用。CBL-b引起了特别的兴趣，因为它被证明是先天免疫系统和获得性免疫系统的关键检查点调节因子，并且缺乏CBL-b的小鼠表现出增强的T细胞杀伤和对肿瘤的自发排斥。因此，与Cblb结合的小分子可能会作为新的免疫检查点调节器。此外，由于Cbl-b是一种E3连接酶，它们也可以作为产生新的、可替代的PROTAC的基础。

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.