Iterative Design and Optimization of Initially Inactive Proteolysis Targeting Chimeras (PROTACs) Identify VZ185 as a Potent, Fast, and Selective von Hippel–Lindau (VHL) Based Dual Degrader Probe of BRD9 and BRD7

Developing
PROTACs to redirect the ubiquitination activity of E3
ligases and potently degrade a target protein within cells can be
a lengthy and unpredictable process, and it remains unclear whether
any combination of E3 and target might be productive for degradation.
We describe a probe-quality degrader for a ligase–target pair
deemed unsuitable: the von Hippel–Lindau (VHL) and BRD9, a
bromodomain-containing subunit of the SWI/SNF chromatin remodeling
complex BAF. VHL-based degraders could be optimized from suboptimal
compounds in two rounds by systematically varying conjugation patterns
and linkers and monitoring cellular degradation activities, kinetic
profiles, and ubiquitination, as well as ternary complex formation
thermodynamics. The emerged structure–activity relationships
guided the discovery of VZ185, a potent, fast, and selective degrader
of BRD9 and of its close homolog BRD7. Our findings qualify a new
chemical tool for BRD7/9 knockdown and provide a roadmap for PROTAC
development against seemingly incompatible target–ligase combinations.