Selectivity and Targeting of G‐Quadruplex Binders Activated by Adaptive Binding and Controlled by Chemical Kinetics

G‐quadruplexes (G4s) are prevalent in oncogenes and are potential antitumor drug targets. However, binding selectivity of compounds to G4s still faces challenges. Herein, we report a platinum(II) complex (Pt1), whose affinity to G4‐DNA is activated by adaptive binding and selectivity controlled by binding kinetics. The resolved structure of Pt1/VEGF‐G4 (a promoter G4) shows that Pt1 matches 3′‐G‐tetrad of VEGF‐G4 through Cl−‐dissociation and loop rearrangement of VEGF‐G4. Binding rate constants are determined by coordination bond breakage/formation, correlating fully with affinities. The selective rate‐determining binding step, Cl−‐dissociation upon G4‐binding, is 2–3 orders of magnitude higher than dsDNA. Pt1 potently targets G4 in living cells, effectively represses VEGF expression, and inhibits vascular growth in zebrafish. We show adaptive G4‐binding activation and controlled by kinetics, providing a complementary design principle for compounds targeting G4 or similar biomolecules. A PtII compound was synthesized and adaptively bound G‐quadruplex DNA through kinetic control. The solution structure of the complex was solved. It was further proved that the compound can target G‐quadruplex in living cells, repress VEGF expression in cancer cells and inhibit blood vessels growth in zebrafish.