Abstract
Molecular glue degraders for therapeutic target proteins are emerging as a strategy in drug discovery. Here, we modify a BRD9 ligand with specific chemical fragments to create degrader compounds that we call Targeted Glues. When bound to the target protein, these create an altered protein-ligand interface that is recognised by a ligase. This interaction between the target and the E3 ligase leads to protein degradation and is stabilised by a reversible covalent interaction between our molecule and a specific cysteine in the ligase. By screening a library of BRD9 targeted compounds we discover AMPTX1, a potent selective and reversibly covalent BRD9 degrader. In cells, AMPTX-1 selectively recruits the E3 ligase, DCAF16, to BRD9 and drives BRD9 degradation, as demonstrated by co-immunoprecipitation-mass spectrometry. BRD9 degradation is primarily dependent on the engagement of the surface Cys58 of DCAF16; the formation of a covalent adduct to DCAF16 is facilitated by ternary complex formation with BRD9. BRD9 degradation is also achieved in vivo with AMPTX-1 in a mouse xenograft model after oral dosing due to the drug-like, orally bioavailable properties of the compound. This supports the concept that covalent recruitment of DCAF16 is a viable approach in the development of therapeutic degraders.