Identification of small molecule binders of the novel cancer immunotherapy target Bird33

There is a crucial need to identify new therapeutic targets for cancer immunotherapy. To address this need, we developed an in vivo CRISPR screening platform in CD8⁺ T cells and identified an E3 ubiquitin ligase we’ll refer to here as Bird33 as a novel negative regulator of CD8⁺ T cell responses in tumors. Bird33 knockout (KO) CD8⁺ T cells attenuated tumor growth in vivo, providing strong rationale for Bird33 as a cancer therapeutic. Bird33 is broadly expressed and has multiple substrates; thus, a prospective therapeutic would need to target the mechanism of Bird33-mediated inhibition of CD8⁺ T cells. We will approach this by: (1) defining the Bird33 surfaces necessary for interaction with two validated targets of Bird33-mediated degradation in CD8⁺ T cells, and (2) performing a DEL screen to identify Bird33 binders. These studies will enable the future identification of chemical compounds that selectively inhibit the interaction of Bird33 with its substrates.