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

05 October 2022, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


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) bromo-domain-targeting degraders based on two scaffolds derived from pyridazinone and pyrimidine-based heterocycles. We evalu-ate 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. Finally, 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, supporting a more challenging target for degradation and a goal for future optimization


nucleosome remodeling

Supplementary materials

Supporting information
This document contains compound characterization, western blots, alpha screen, and NanoBRET data.


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