Figure 1.

DB270 and DB1976: two isosteres with contrasting inhibitory efficacy on the transcription factor PU.1. (A) DB270 and DB1976 are classic heterocyclic dications with strong affinity and selectivity for AT-rich sequences commonly found in cognate DNA binding sites for PU.1. (B) Despite similar DNA-binding properties on their own, the two isosteres differ markedly in their ability to inhibit PU.1. When inhibition of PU.1 binding to the λB motif (5′-AATAAAAGGAAGTG-3′), a natural high-affinity DNA binding site, was measured by biosensor-SPR, only DB1976 effectively displaced with DNA-bound PU.1 (5). The poor inhibitory efficacy seen with DB270 indicated additional non-competitive interactions at work.