Proteome‐Wide Ligand and Target Discovery by Using β ‐Nitrostyrene Electrophiles: Supporting Targeted Protein Degradation

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Abstract Bioconjugation chemistry has been a powerful avenue in expanding the repertoire of druggable proteome, as well as in identifying new E3 ligases to support targeted protein degradation (TPD). However, a large fraction of proteome remains inaccessible with existing covalent probes. Herein, we incorporated various electron‐withdrawing groups into styrene derivatives and identified β ‐nitrostyrene as a cysteine‐targeting reversible covalent warhead for target discovery. Through phenotypic screening and chemoproteomics platforms, we identified new ligandable sites such as C96 of SND1, C110 of PTGES2, modulating cell proliferation in an acute myeloid leukemia cell line. Moreover, incorporation of this warhead into the BRD4 inhibitor (+)‐JQ1 demonstrated that the covalent handle engages the novel E3 ligase tripartite motif‐containing 28 (TRIM28) at Cys232 residue, thereby promoting the targeted degradation. Notably, when transplanted into other protein‐targeting ligands, the β ‐nitrostyrene warhead effectively induced protein degradation of EGFR L858R/T790M/C797S , PDE5, BTK, LRRK2, and BCR‐ABL/c‐ABL without eliciting a hook effect. Importantly, the degraders demonstrate significantly enhanced antcancer effects compared to corresponding inhibitors. To our knowledge, this is the first report of small‐molecular degraders engaging TRIM28 to support targeted protein degradation, and provides a rational pathway for design and development of potent monovalent degraders.

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