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c-Myc is a major oncogene that is estimated to result in almost all human cancers and the c-Myc downregulation has become an attractive strategy for cancer treatment. For it is hard to design compounds that can directly interact with the c-Myc protein, the DNA G-quadruplex (G4) was discovered in its promoter region which was referred to as a potential drug target for controlling c-Myc expression. In this study, a combined strategy of molecular docking-based virtual screening, molecular dynamics (MD) simulation, and molecular mechanics/generalized Born surface area (MM/GBSA) free energy calculation was conducted on the existing FDA-Approved Drugs Library, eight compounds were selected for further experimental assay. Among them, five compounds exhibited dose-dependently anticancer activities against RPMI-8226 cells with IC 50 values less than 18.4 μM. Further experiments showed that Trovafloxacin, Ozanimod, and Ozenoxacin decreased c-Myc mRNA level obviously and downregulated c-Myc expression significantly. In summary, compounds Trovafloxacin, Ozanimod, and Ozenoxacin might be regarded as new c-Myc G4 stabilizers for the treatment of c-Myc related cancers in the future., (© 2022 Wiley-VCH GmbH.)

G-quadruplex (G4), present in the c-Myc promoter, has emerged as an attractive cancer-specific molecular target for drug development. So, the discovery of small molecules to stabilize c-Myc-G4 to inhibit transcription of c-Myc protein is of great significance. Herein, a combined molecular docking-based virtual screening strategy, molecular dynamics (MD) simulation, and molecular mechanics/generalized Born surface area (MM/GBSA) free energy calculation was conducted on the existing L6000 Natural Compound Library. Four natural compounds, including Licoflavone B, Demethyleneberberine, Ginkgetin, and Mulberroside C, were predicted to have preferable binding affinities to c-Myc G4 and then selected for commercial purchase and experimental evaluation. Compounds Licoflavone B and Ginkgetin can significantly inhibit myeloma cell proliferation, with IC 50 values <8 μM against the RPMI-8226 cell line. Moreover, our data demonstrated that the two compounds could simultaneously downregulate c-Myc transcription and expression. Collectively, compounds Licoflavone B and Ginkgetin might be regarded as new candidates for the development of the more potent c-Myc-G4 stabilizers in the future., (© 2022 John Wiley & Sons A/S.)

• Identification of benzimidazolyl isoxazole derivatives as new potent c-Myc G4 stabilizers. • Compound 3-(1-(2-(3,5-dimethylphenoxy)ethyl)-1H-benzo[d]imidazol-2-yl)-5-(4-fluorophenyl)isoxazole (EP12) exhibited better RPMI-8226 cell inhibition activity (IC 50 = 6.16 µM). • Compound EP12 induced apoptosis and inhibited the expression of c-Myc mRNA and c-Myc protein at 5 µM.. • Circular dichroism (CD) and molecular dynamics (MD) simulation studies indicated that compound EP12 could firmly stabilize c-Myc G4. The c-Myc oncogene is one of the most frequently deregulated driver genes in human cancer, and its rearrangement is closely associated with the development of multiple myeloma (MM). However, c-Myc is a disordered protein that lacks adequate binding pockets on its surface and has a half-life of only 20 to 30 minutes, so it is challenging to design small-molecule inhibitors. The guanine-rich nuclease hypersensitive element III 1 (NHEIII 1) upstream of the P1 promoter of the c-Myc gene can form intramolecular parallel G-quadruplexes (G4) structures. It has been established that c-Myc G4 controls 85-90% of the transcriptional activation of the c-Myc, which represents one of the most sought-after drug targets in cancer. Therefore, targeting c-Myc G4 to inhibit c-Myc protein would be a potential strategy for the treatment of MM. Herein, a series of benzimidazolyl isoxazole derivatives (EP1-EP19) were designed and synthesized. Among them, compound EP12 exhibited better RPMI-8226 cell inhibition activity (IC 50 = 6.16 µM). Moreover, compound EP12 induced apoptosis and inhibited the expression of c-Myc mRNA and c-Myc protein at 5 µM. Circular dichroism (CD) and molecular dynamics (MD) simulation studies indicated that compound EP12 could firmly stabilize c-Myc G4. Accordingly, compound EP12 displayed potent anti-MM activities in vitro and might be a potential c-Myc G4 small molecular stabilizer to warrant further investigation. [Display omitted] [ABSTRACT FROM AUTHOR]