Perturbation of the c-Myc-Max protein-protein interaction via synthetic α-helix mimetics.
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 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 μM. 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.
†Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 North Pine Street, Baltimore, Maryland 21201, United States.
Kwan-Young
KY
Jung
‡Section of Hematology/Oncology, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC Pittsburgh, Pittsburgh, Pennsylvania 15224, United States.
Huabo
H
Wang
§Cell Death and Survival Networks Research Program, NCI-Designated Cancer Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, United States.
Peter
P
Teriete
†Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 North Pine Street, Baltimore, Maryland 21201, United States.
Jeremy L
JL
Yap
†Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 North Pine Street, Baltimore, Maryland 21201, United States.
Lijia
L
Chen
†Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 North Pine Street, Baltimore, Maryland 21201, United States.
Maryanna E
ME
Lanning
‡Section of Hematology/Oncology, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC Pittsburgh, Pittsburgh, Pennsylvania 15224, United States.
Angela
A
Hu
§Cell Death and Survival Networks Research Program, NCI-Designated Cancer Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, United States.
Lester J
LJ
Lambert
∥KG Jebsen Center for Myeloma Research and Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim NO-7491, Norway.
Toril
T
Holien
∥KG Jebsen Center for Myeloma Research and Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim NO-7491, Norway.
Anders
A
Sundan
§Cell Death and Survival Networks Research Program, NCI-Designated Cancer Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, United States.
Nicholas D P
ND
Cosford
‡Section of Hematology/Oncology, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC Pittsburgh, Pittsburgh, Pennsylvania 15224, United States.
Edward V
EV
Prochownik
†Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 North Pine Street, Baltimore, Maryland 21201, United States.|⊥University of Maryland Greenebaum Cancer Center, 22 South Greene Street, Baltimore, Maryland 21201, United States.
Steven
S
Fletcher
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000737:chemistry* / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D024202:Electrophoretic Mobility Shift Assay; D018257:Helix-Loop-Helix Motifs; D006801:Humans; D020128:Inhibitory Concentration 50; D018716:Molecular Mimicry; D019906:Nuclear Magnetic Resonance, Biomolecular; D055503:Protein Multimerization; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D020349:Surface Plasmon Resonance
D000970:Antineoplastic Agents; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C499330:MAX protein, human; D016271:Proto-Oncogene Proteins c-myc; D054852:Small Molecule Libraries