Direct inhibition of c-Myc-Max heterodimers by celastrol and celastrol-inspired triterpenoids

摘要: // Huabo Wang 1 , Peter Teriete 2 Angela Hu Dhanya Raveendra-Panickar Kelsey Pendelton John S. Lazo 3 Julie Eiseman 4,5 Toril Holien 6 Kristine Misund Ganna Oliynyk 7 Marie Arsenian-Henriksson Nicholas D. P. Cosford Anders Sundan and Edward V. Prochownik 1,5,8 Section of Hematology/Oncology, Children’s Hospital Pittsburgh UPMC, The University Medical Center, Pittsburgh, PA, USA Cell Death Survival Networks Research Program, Sanford Burnham Prebys Discovery Institute, La Jolla, CA, Department Pharmacology, Virginia School Medicine, Charlottesville, Virginia, 4 Chemical Biology 5 Cancer Molecular Medicine K. G. Jebsen Center for Myeloma Research, Norwegian Science Technology, Trondheim, Norway Microbiology Tumor Biology, Karolinska Institutet, Stockholm, Sweden 8 Genetics, Correspondence to: Prochownik, email: Keywords : 10058-F4, 10074-G5, BET inhibitors, myeloma, neuroblastoma, quinone methide Received September 24, 2015 Accepted 26, Published October 14, Abstract Many oncogenic signals originate from abnormal protein-protein interactions that are potential targets small molecule inhibitors. However, the therapeutic disruption these has proved elusive. We report here naturally-occurring triterpenoid celastrol is an inhibitor c-Myc (Myc) oncoprotein, which over-expressed in many human cancers. Most Myc inhibitors prevent association between its obligate heterodimerization partner Max via their respective bHLH-ZIP domains. In contrast, we show binds to alters quaternary structure pre-formed dimer abrogates DNA binding. Celastrol contains a reactive group promiscuously forms Michael adducts with numerous target proteins other free sulfhydryl-containing molecules. Interestingly, derivatives lacking showed enhanced specificity potency against Myc. As analogs rapidly reduced abundance protein provoked global energy crisis marked by ATP depletion, neutral lipid accumulation, AMP-activated kinase activation, cell cycle arrest apoptosis. They also inhibited proliferation established cancer lines as well primary myeloma explants were otherwise resistant JQ1, potent indirect inhibitor. N-Myc amplified neuroblastoma cells similar responses and, additional, underwent neuronal differentiation. These studies indicate certain pharmacologically undesirable properties such adduct formation can be eliminated while increasing selectivity toward N-Myc. This, together low vivo toxicity, provides strong rationale pursuing development additional Myc-specific derivatives.