AT-rich DNA minor groove at PU.1 binding sites

The AT-rich DNA minor groove at PU.1 binding sites is a specialized genomic region that serves as a therapeutic target for modulating the activity of the PU.1 (SPI1) transcription factor (Antony-Debré et al., 2017, JCI). PU.1 is a member of the ETS family and acts as a master regulator of myeloid and B-cell development, but its dysregulation is a primary driver in the pathogenesis of acute myeloid leukemia (AML) (Munde et al., 2014, Nucleic Acids Res). Because transcription factors like PU.1 lack traditional small-molecule binding pockets, researchers have targeted the specific DNA sequences they recognize to disrupt their function (Stephens et al., 2016, J Med Chem). Small molecules such as heterocyclic diamidines (e.g., DB1976) are designed to bind with high affinity to the AT-rich minor groove adjacent to the PU.1 consensus sequence. By occupying this groove, these compounds effectively displace PU.1 or prevent its recruitment to target genes, thereby inhibiting the pro-proliferative and anti-differentiative gene expression programs associated with leukemogenesis (Poon et al., 2021, Bioorg Med Chem). This approach offers a strategy to target the DNA-protein interaction rather than the protein itself, providing a potential therapeutic avenue for transcription-factor-driven cancers.

Other names

PU.1-DNA interfaceSPI1 binding site minor grooveAT-rich minor groove of PU.1 response elements

Competitive or allosteric inhibition of PU.1 transcription factor binding through high-affinity occupancy of the adjacent AT-rich DNA minor groove (Munde et al., 2014; Antony-Debré et al., 2017).