Discovery of First-in-Class BAZ2A/B and BAZ2B-Selective Degraders

Bromodomain adjacent to zinc finger 2A and 2B (BAZ2A and BAZ2B) are homologous proteins that serve as regulatory subunits in different initiation switch complexes. Despite their structural similarity, BAZ2A/B seem to play different roles in disease development. However, reported BAZ2A/B inhibitors bind similarly to both homologues. Here we report the discovery of dBAZ2 and dBAZ2B, first-in-class Proteolysis Targeting Chimeras (PROTACs) degrading BAZ2A/B and BAZ2B, respectively. dBAZ2 induces BAZ2A/B degradation with a D _max ≥ 97% (BAZ2A_DC₅₀ = 180 nM; BAZ2B_DC₅₀ = 250 nM), while dBAZ2B selectively degrades BAZ2B with a DC₅₀ = 19 nM and D _max ≥ 97%. Degradation by dBAZ2 and dBAZ2B is almost complete within 2 h, is maintained for at least 3 days, and occurs in PC3 and MM1S cells, demonstrating the potential of these compounds as chemical probes to decipher the distinct biological functions of BAZ2A/B.