TARGETING E2F1-DNA COMPLEXES WITH MICROGONOTROPEN DNA-BINDING AGENTS

Microgonotropen (MGT) DNA binding drugs, which consist of an A+T-selec tive DNA minor groove binding tripyrrole peptide and polyamine chains attached to a central pyrrole that extend drug contact into the DNA ma jor groove, were found to be extraordinarily effective inhibitors of E 2 factor 1 (E2F1) association with its DNA promoter element (5'-TTTCGC GCCAAA). The most active of these drugs, MGT-6a, was three orders of m agnitude more effective than distamycin and inhibited complexes betwee n E2F1 and the dihydrofolate reductase promoter by 50% at 0.00085 mu M . A relationship was found between the measured equilibrium constants for binding of MGTs to the A+T region of d(GGCGA(3)T(3)GGC)/d(CCGCT(3) A(3)CCG) and their inhibition of complex formation between E2F1 and th e DNA promoter element, A representative of the potent MGT inhibitors was significantly more active on inhibition of E2F1-DNA complex format ion compared with disruption of a preexisting complex.