Structure-based discovery of Licoflavone B and Ginkgetin targeting c-Myc G-quadruplex to suppress c-Myc transcription and myeloma growth.

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.