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.
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We thank the members of the Bradner and Gray labs for engaging scientific conversations. We also thank J. Wang (Dana-Farber Cancer Institute) for her help with chemical characterization. Lastly, we would like to thank S.A. Armstrong and K. Stegmaier (Dana-Farber Cancer Institute) for kindly providing us with materials. This research was supported by a Starr Cancer Consortium Grant (J.E.B.) and NIH/NCI P01CA066996 (J.E.B.). L.N.G is supported by an NSF GRFP fellowship (2016222867). D.L.B. was supported by the Claudia Adams Barr Program in Innovative Basic Cancer Research and is a Merck Fellow of the Damon Runyon Cancer Research Foundation (DRG-2196-14). Quantitative proteomics studies were performed by R. Kunz of the Thermo Fisher Scientific Center for Multiplexed Proteomics at Harvard Medical School.
D.L.B. and J.P. are now employees of Novartis. N.S.G. is a Scientific Founder and member of the Scientific Advisory Board of C4 Therapeutics. J.E.B. is a Scientific Founder of C4 Therapeutics. J.E.B. is now an executive and shareholder in Novartis AG.
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Gechijian, L.N., Buckley, D.L., Lawlor, M.A. et al. Functional TRIM24 degrader via conjugation of ineffectual bromodomain and VHL ligands. Nat Chem Biol 14, 405–412 (2018). https://doi.org/10.1038/s41589-018-0010-y
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