The BET degrader BETd-246 demonstrated significant anti-tumor efficacy in T-cell acute lymphoblastic leukemia by inhibiting TRAT1.

T cell acute lymphoblastic leukemia (T-ALL) is a rare lymphoblastic leukemia characterized by T lymphocyte heterogeneity and diverse genetic abnormalities, accounting for approximately 15% of childhood leukemias. BETd-246 serves as a tethering agent that links BETi-211 to thalidomide for the development of BET degraders. This compound has demonstrated superior efficacy in tumor treatment compared with traditional BET inhibitors. However, the anti-tumor effects and molecular mechanisms underlying the action of BETd-246 in T-ALL remain poorly understood. The aim of our study was to investigate the anti-tumor effects of BETd-246 and provide new insights into treatment strategies for T-ALL. In human T-ALL cell lines, BETd-246 induced degradation of BET proteins, particularly BRD4, at nanomolar concentrations. It effectively inhibited cell growth, disrupted the cell cycle, and promoted apoptosis in T-ALL cells in a concentration-dependent manner. The effects of BETd-246 were more pronounced than those of JQ1. In vivo experiments revealed that treatment with BETd-246 reduced proliferation and invasion of T-ALL cells and extended survival time in mouse models. RNA sequencing analysis indicated significant downregulation of T-cell receptor (TCR)-associated transmembrane adaptor 1 (TRAT1) expression in T-ALL cells treated with BETd-246. Knocking down TRAT1 resulted in increased growth inhibition and enhanced apoptosis within these cells. These findings suggest that TRAT1 plays a crucial role in mediating the effects of BETd-246 in T-ALL. Overall, our results indicate that BETd-246 is a promising therapeutic agent for treating this aggressive form of leukemia.