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

G-quadruplexes (G4s) are prevalent in oncogenes and proposed to be 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) reveals 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 and correlate fully with affinities. The selective rate-determining binding step, Cl - -dissociation upon G4-binding which is 2~3 orders of magnitude higher than dsDNA. We further demonstrate that Pt1 potently targets G4 in living cells, effectively represses VEGF expression and inhibits vascular growth in zebrafish. We present adaptive G4-binding activation and selectivity controlled by kinetics, providing a complementary design principle for compounds targeting G4 or similar biomolecules.