Mode of action of a DCAF16-recruiting targeted glue that can selectively degrade BRD9

TY - JOUR

T1 - Mode of action of a DCAF16-recruiting targeted glue that can selectively degrade BRD9

AU - Hughes, Scott J.

AU - Stec, Wojciech J.

AU - Davies, Colin T.R.

AU - McGarry, David

AU - Williams, Alicia

AU - Carrara, Marta

AU - Del Barco Barrantes, Ivan

AU - Harris, Rebecca

AU - Tasegian, Anna

AU - Owens, Dominic D.G.

AU - Fawcett, Alexander

AU - Hellicar, John

AU - Azevedo, Aleksandra

AU - Meier, Gregor P.

AU - Runcie, Andrew C.

AU - Greger, Liliana

AU - O’Rourke, Martin

AU - Churcher, Ian

AU - Pass, Martin

AU - Brown, Giles A.

AU - Ciulli, Alessio

AU - Modis, Louise K.

AU - Testa, Andrea

N1 - Publisher Copyright: © The Author(s) 2025.

PY - 2025/12

Y1 - 2025/12

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/105019750122

U2 - 10.1038/s41467-025-63594-w

DO - 10.1038/s41467-025-63594-w

M3 - Article

C2 - 41145412

AN - SCOPUS:105019750122

SN - 2041-1723

VL - 16

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 8516

ER -