Sulfinyl Aziridines as Stereoselective Covalent Destabilizing Degraders of the Oncogenic Transcription Factor MYC.

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 MYC in vitro as pure MYC/MAX protein complex and in situ in cancer cells to destabilize MYC, inhibit MYC transcripti

SUBMITTER: Rosen HT 

PROVIDER: S-EPMC11888305 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature