2. Academic Validation
  3. Discovery of a Functional Covalent Ligand Targeting an Intrinsically Disordered Cysteine within MYC

Discovery of a Functional Covalent Ligand Targeting an Intrinsically Disordered Cysteine within MYC

  • Cell Chem Biol. 2021 Jan 21;28(1):4-13.e17. doi: 10.1016/j.chembiol.2020.09.001.
Lydia Boike 1,  Alexander G Cioffi 1,  Felix C Majewski 1,  Jennifer Co 1,  Nathaniel J Henning 1,  Michael D Jones 2,  Gang Liu 2,  Jeffrey M McKenna 2,  John A Tallarico 2,  Markus Schirle 2,  Daniel K Nomura 3
Affiliations

Affiliations

  • 1 Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA 94720, USA.
  • 2 Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA 94720, USA; Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
  • 3 Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA 94720, USA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Innovative Genomics Institute, Berkeley, CA 94720, USA. Electronic address: [email protected].
PMID: 32966806 DOI: 10.1016/j.chembiol.2020.09.001
Abstract

MYC is a major oncogenic transcriptional driver of most human cancers that has remained intractable to direct targeting because much of MYC is intrinsically disordered. Here, we have performed a cysteine-reactive covalent ligand screen to identify compounds that could disrupt the binding of MYC to its DNA consensus sequence in vitro and also impair MYC transcriptional activity in situ in cells. We have identified a covalent ligand, EN4, that targets cysteine 171 of MYC within a predicted intrinsically disordered region of the protein. We show that EN4 directly targets MYC in cells, reduces MYC and MAX thermal stability, inhibits MYC transcriptional activity, downregulates multiple MYC transcriptional targets, and impairs tumorigenesis. We also show initial structure-activity relationships of EN4 and identify compounds that show improved potency. Overall, we identify a unique ligandable site within an intrinsically disordered region of MYC that leads to inhibition of MYC transcriptional activity.

Keywords

MYC; activity-based protein profiling; chemoproteomics; covalent ligand; cysteine; intrinsically disordered; transcription factor; undruggable.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-134761
    Covalent Ligand of c-MYC