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Abstract While MYC is a significant oncogenic transcription factor driver of cancer, directly targeting MYC has remained challenging due to its intrinsic disorder and poorly defined structure, deeming it “undruggable.” Whether transient pockets formed within intrinsically disordered and unstructured regions of proteins can be selectively targeted with small molecules remains an outstanding challenge. Here, we developed a bespoke stereochemically-paired spirocyclic oxindole aziridine covalent library and screened this library for degradation of MYC. Through this screen, we identified a hit covalent ligand KL2-236, bearing a unique sulfinyl aziridine warhead, that engaged MYCin vitroas pure MYC/MAX protein complex andin situin cancer cells to destabilize MYC, inhibit MYC transcriptional activity and degrade MYC in a proteasome-dependent manner through targeting intrinsically disordered C203 and D205 residues. Notably, this reactivity was most pronounced for specific stereoisomers of KL2-236 with a diastereomer KL4-019 that was largely inactive. Mutagenesis of both C203 and D205 completely attenuated KL2-236-mediated MYC degradation. We have also optimized our initial KL2-236 hit compound to generate a more durable MYC degrader KL4-219A in cancer cells. Our results reveal a novel ligandable site within MYC and indicate that certain intrinsically disordered regions within high-value protein targets, such as MYC, can be interrogated by isomerically unique chiral small molecules, leading to destabilization and degradation. 

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