DB1976 is a selenophene analog of DB270 and a highly potent, cell-permeable, fully efficacious transcription factor PU.1 inhibitor. It effectively inhibits PU.1 binding (IC50 of 10 nM) and strongly inhibits the PU.1/DNA complex (with high DB1976-λB affinity, KD of 12 nM) in vitro. Additionally, DB1976 has an apoptosis-inducing effect.

PU.1:10 nM

DB1976 is a heterocyclic dication possessing a strong affinity and selectivity for AT-rich sequences in DNA, which are crucial for the binding of transcription factor PU.1. It effectively inhibits the activation mediated by PU.1 in a dose-dependent manner, displaying an IC50 of 2.4 μM in PU.1-negative HEK293 cells. Importantly, DB1976 significantly reduces the growth of PU.1 URE–/– AML cells, with an IC50 of 105 μM, while minimally affecting normal hematopoietic cells (IC50 of 334 μM). Treatment with DB1976 results in a notable increase in apoptosis, particularly a 1.6-fold rise in murine PU.1 URE–/– AML cells and similar outcomes in human MOLM13 cells. Furthermore, DB1976 dramatically reduces the viability (by 81%) and clonogenic capacity (by 36%) of primary human AML cells compared to those treated with a vehicle, alongside effecting a 1.5-fold increase in the apoptotic cell fraction.