The addressable pocket of a protein is often not functionally relevant in disease. This is true for the multidomain, bromodomain-containing transcriptional regulator TRIM24. TRIM24 has been posited as a dependency in numerous cancers, yet potent and selective ligands for the TRIM24 bromodomain do not exert effective anti-proliferative responses. We therefore repositioned these probes as targeting features for heterobifunctional protein degraders. Recruitment of the VHL E3 ubiquitin ligase by dTRIM24 elicits potent and selective degradation of TRIM24. Using dTRIM24 to probe TRIM24 function, we characterize the dynamic genome-wide consequences of TRIM24 loss on chromatin localization and gene control. Further, we identify TRIM24 as a novel dependency in acute leukemia. Pairwise study of TRIM24 degradation versus bromodomain inhibition reveals enhanced anti-proliferative response from degradation. We offer dTRIM24 as a chemical probe of an emerging cancer dependency, and establish a path forward for numerous selective yet ineffectual ligands for proteins of therapeutic interest.

蛋白质的可寻址口袋通常与疾病在功能上不相关。对于多结构域，含溴结构域的转录调节子TRIM24而言，这是正确的。TRIM24被认为是多种癌症的依赖性，但是TRIM24溴结构域的有效和选择性配体不能发挥有效的抗增殖反应。因此，我们将这些探针重新定位为异双功能蛋白降解物的靶向特征。dTRIM24招募VHL E3泛素连接酶会引发TRIM24的有效和选择性降解。使用dTRIM24探测TRIM24功能，我们表征了TRIM24缺失对染色质定位和基因控制的动态全基因组后果。此外，我们确定TRIM24为急性白血病的新型依赖。TRIM24降解与溴结构域抑制的成对研究表明，降解可增强抗增殖反应。我们提供dTRIM24作为新兴癌症依赖性的化学探针，并为治疗性蛋白质的众多选择性但无效的配体建立了前进的道路。