Targeting MYC with modular synthetic transcriptional repressors derived from bHLH DNA-binding domains. Journal Article

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Authors: Speltz, TE; Qiao, Z; Swenson, CS; Shangguan, X; Coukos, JS; Lee, CW; Thomas, DM; Santana, J; Fanning, SW; Greene, GL; Moellering, RE
Article Title: Targeting MYC with modular synthetic transcriptional repressors derived from bHLH DNA-binding domains.
Abstract: Despite unequivocal roles in disease, transcription factors (TFs) remain largely untapped as pharmacologic targets due to the challenges in targeting protein-protein and protein-DNA interactions. Here we report a chemical strategy to generate modular synthetic transcriptional repressors (STRs) derived from the bHLH domain of MAX. Our synthetic approach yields chemically stabilized tertiary domain mimetics that cooperatively bind the MYC/MAX consensus E-box motif with nanomolar affinity, exhibit specificity that is equivalent to or beyond that of full-length TFs and directly compete with MYC/MAX protein for DNA binding. A lead STR directly inhibits MYC binding in cells, downregulates MYC-dependent expression programs at the proteome level and inhibits MYC-dependent cell proliferation. Co-crystallization and structure determination of a STR:E-box DNA complex confirms retention of DNA recognition in a near identical manner as full-length bHLH TFs. We additionally demonstrate structure-blind design of STRs derived from alternative bHLH-TFs, confirming that STRs can be used to develop highly specific mimetics of TFs targeting other gene regulatory elements.
Journal Title: Nature biotechnology
Publisher: Unknown  
Date Published: 2022