Discovery of Non-Degradative Covalent Molecular Glues for Transcriptional Reprogramming.

ABSTRACT: Transcriptional reprogramming through induced proximity has emerged as a powerful strategy for modulating the expression of oncogenic and tumor-suppressive genes. Inspired by transcriptional reprogramming approaches such as transcriptional/epigenetic chemical inducers of proximity (TCIPs) that link BCL6 inhibitors to transcriptional regulators, we sought to develop covalent ligands that rewire BCL6 proximity to selectively suppress MYC transcriptional output while derepressing BCL6 target loci. Through a chemistry-driven and chemoproteomics-enabled design strategy, we generated a panel of BCL6-based electrophile-bearing hybrid ligands and identified a nondegradative molecular glue, ZD-1-186, that potently suppresses MYC and robustly induces CDKN1A (p21) in diffuse large B-cell lymphoma cel

SUBMITTER: Duong TN 

PROVIDER: S-EPMC12710638 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature