NUT Inhibitors

NUT inhibitors comprise a chemical class primarily centered around the inhibition of bromodomain and extra-terminal (BET) proteins, particularly BRD4, which is a crucial interacting partner of the NUT protein. This interaction is especially significant in the context of NUT midline carcinoma, where a BRD4-NUT fusion gene commonly drives the oncogenic process. The compounds listed, such as JQ1, I-BET151, and OTX015, operate by occupying the acetyl-lysine recognition pocket of BRD4, which prevents the protein from effectively engaging with acetylated histones and other proteins, including NUT. This disruption impedes the formation of the BRD4-NUT complex, leading to the alteration of gene expression patterns typically regulated by this complex.

The approach to inhibiting the NUT protein is indirect; it involves the modulation of the chromatin landscape and transcriptional regulation, rather than direct inhibition of NUT itself. Compounds like CPI-0610 and MS417, which selectively target BRD4, can lead to changes in the expression of genes that are dysregulated by the BRD4-NUT fusion. Other molecules, for example, dBET1, take a different approach by promoting the degradation of BRD4, thereby removing the protein from the transcriptional machinery it forms with NUT. Similarly, ABBV-744's selective inhibition of the BRD4 BD2 domain offers a more targeted disruption of the BRD4-related transcriptional dysregulation. By focusing on the BET bromodomains, inhibitors such as ZBC260 and PLX51107 demonstrate an ability to alter the recruitment of transcriptional regulators and, as a result, the downstream gene expression profiles. The chemical diversity of these inhibitors, including small molecule BET inhibitors like RVX-208 and GSK525762A, reflects the dynamic approach to modulating the epigenetic readers that influence NUT's role in chromatin remodeling and transcriptional control.