Unknown

Dataset Information

0

Perturbation of the c-Myc-Max protein-protein interaction via synthetic ?-helix mimetics.


ABSTRACT: The rational design of inhibitors of the bHLH-ZIP oncoprotein c-Myc is hampered by a lack of structure in its monomeric state. We describe herein the design of novel, low-molecular-weight, synthetic ?-helix mimetics that recognize helical c-Myc in its transcriptionally active coiled-coil structure in association with its obligate bHLH-ZIP partner Max. These compounds perturb the heterodimer's binding to its canonical E-box DNA sequence without causing protein-protein dissociation, heralding a new mechanistic class of "direct" c-Myc inhibitors. In addition to electrophoretic mobility shift assays, this model was corroborated by further biophysical methods, including NMR spectroscopy and surface plasmon resonance. Several compounds demonstrated a 2-fold or greater selectivity for c-Myc-Max heterodimers over Max-Max homodimers with IC50 values as low as 5.6 ?M. Finally, these compounds inhibited the proliferation of c-Myc-expressing cell lines in a concentration-dependent manner that correlated with the loss of expression of a c-Myc-dependent reporter plasmid despite the fact that c-Myc-Max heterodimers remained intact.

SUBMITTER: Jung KY 

PROVIDER: S-EPMC4955407 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

altmetric image

Publications


The rational design of inhibitors of the bHLH-ZIP oncoprotein c-Myc is hampered by a lack of structure in its monomeric state. We describe herein the design of novel, low-molecular-weight, synthetic α-helix mimetics that recognize helical c-Myc in its transcriptionally active coiled-coil structure in association with its obligate bHLH-ZIP partner Max. These compounds perturb the heterodimer's binding to its canonical E-box DNA sequence without causing protein-protein dissociation, heralding a ne  ...[more]

Similar Datasets

| S-EPMC9147657 | biostudies-literature
| S-EPMC6591138 | biostudies-literature
| S-EPMC6005445 | biostudies-literature
| S-EPMC4253403 | biostudies-literature
| S-EPMC6593395 | biostudies-literature
| S-EPMC3263801 | biostudies-literature
| S-EPMC6030159 | biostudies-literature
2023-05-23 | GSE224589 | GEO
| S-EPMC3592999 | biostudies-literature
| S-EPMC3079198 | biostudies-literature