Discovery of a Functional Covalent Ligand Targeting an Intrinsically Disordered Cysteine within MYC.
Cell Chem Biol
; 28(1): 4-13.e17, 2021 01 21.
Article
en En
| MEDLINE
| ID: mdl-32966806
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.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Proteínas Proto-Oncogénicas c-myc
/
Cisteína
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Cell Chem Biol
Año:
2021
Tipo del documento:
Article
País de afiliación:
Estados Unidos