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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 IC50 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. [ABSTRACT FROM AUTHOR]

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 IC50 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. [ABSTRACT FROM AUTHOR]