CX-5461 is a potent DNA G-quadraplex (G4) stabilizer currently in Phase II human clinical trials showing a promising anti-cancer ability through selectively targeting G4 at telomere ends and promoter regions of oncogenes such as c-kit1 and c-Myc. Although the high resolution structure of a human telomeric G4 (PBD ID: 1KF1), c-kit1 (PBD ID: 4WO3), c-Myc promoter G4s (PBD ID: 2MGN) and DNA duplex are available, their complexes with CX-5461 are not available. To decipher the binding pose and mechanism of CX-5461 to the G4s and duplex and elucidate the origin of selectivity of CX-5461 to G4s over the DNA duplex, we carried out free ligand binding molecular dynamics simulations for a total of 60 µS( 4x15 µS). Our trajectory clustering and MM-PBSA binding energy analyses was able to identify the major binding poses of the three G4s as top intercalation and bottom stacking, and the major binding mode of the DNA duplex as groove binding. Order parameters were calculated to provide details of each complexes unique binding pathway. Interestingly, each G4 complex repeatedly showed CX-5461 binding to the G4, a base flipping outward to make room, followed by that same base flipping back on top of CX-5461 intercalating it into the G4. These suggest an induced fit binding mechanism to the G4s by CX-5461. The MM/PBSA analysis identified the order of stability of each complex from high to low as the human telomeric G4, the c-kit1 G4, the c-Myc G4, and DNA duplex system respectively, which was consistent with the decreasing order of their melting temperatures measured from the experiments. CX-5461 was able to intercalate into all G4 systems but was not able to intercalate into the DNA duplex system, explaining the selectivity of CX-5461 to the G4 over the DNA duplex. The findings from this study provide insights for optimizing this class of anti-cancer drugs.

Binding mechanism of CX-5461 to human telomeric, c-kit1 and c-Myc promoter G-quadruplexes, and a DNA duplex using free ligand molecular dynamics simulations

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.