TMX1 is a covalent, selective BRD4 molecular glue degrader. TMX1 binds to the JQ1-binding site of BRD4BD2 , forms covalent bonds with Cys58 of DCAF16 and Cys87 of GAK in a BRD4BD2 -dependent template-assisted manner, stabilizes the BRD4 -TMX1- DCAF16 ternary complex, and promotes the ubiquitination of BRD4 via the CRL4 DCAF16 ubiquitin ligase complex. TMX1 induces selective degradation of BRD4 , mild degradation of BRD2 and BRD3 , as well as DCAF16-dependent cytotoxicity.
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