ABSTRACT
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.
Subject(s)
Chromatin Assembly and Disassembly , Transcription Factors , Humans , Protein DomainsABSTRACT
The steric and electronic drivers of regioselectivity in platinum-catalyzed intramolecular hydroalkoxylation are elucidated. A branch point is found that divides the process between 5-exo and 6-endo selective processes, and enol ethers can be accessed in good yields for both oxygen heterocycles. The main influence arises from an electronic effect, where the alkyne substituent induces a polarization of the alkyne that leads to preferential heteroatom attack at the more electron-deficient carbon. The electronic effects are studied in other contexts, including hydroacyloxylation and hydroamination, and similar trends in directionality are predominant although not uniformly observed.
