Design of Class I/IV Bromodomain-Targeting Degraders for Chromatin Remodeling Complexes

• Published in: ACS chemical biology 2023-06, Vol.18 (6), p.1278-1293
• Main Authors: Zahid, Huda, Costello, Jeff P., Li, Yao, Kimbrough, Jennifer R., Actis, Marisa, Rankovic, Zoran, Yan, Qin, Pomerantz, William C. K.
• Format: Article
• Language: English
• Subjects: Chromatin Assembly and Disassembly; Humans; Protein Domains; Transcription Factors
• ISSN: 1554-8929; 1554-8937
• DOI: 10.1021/acschembio.2c00902

Targeted protein degradation is an emerging technology that can be used for modulating the activity of epigenetic protein targets. Among bromodomain-containing proteins, a number of degraders for the BET family have been developed, while non-BET bromodomains remain underexplored. Several of these proteins are subunits in chromatin remodeling complexes often associated with oncogenic roles. Here, we describe the design of class I (BPTF and CECR2) and IV (BRD9) bromodomain-targeting degraders based on two scaffolds derived from pyridazinone and pyrimidine-based heterocycles. We evaluate various exit vectors and linkers to identify analogues that demonstrate selectivity within these families. We further use an in-cell NanoBRET assay to demonstrate that these heterobifunctional molecules are cell-permeable, form ternary complexes, and can degrade nanoluciferase–bromodomain fusions. As a first example of a CECR2 degrader, we observe that our pyrimidine-based analogues degrade endogenous CECR2 while showing a smaller effect on BPTF levels. The pyridazinone-based compounds did not degrade BPTF when observed through Western blotting, further supporting a more challenging target for degradation and a goal for future optimization.