Transcription factors (TFs) are proteins required for gene expression and, more precisely, to control gene transcription. Transcriptional factors can be altered or dysregulated to mediate aberrant gene expression, including the inhibition of differentiation and cell death gene expression programs, hallmarks of cancer. Many cancer types affect transcription factor activity directly.

Several regulatory networks that control gene expression are better understood than ever before. It is suggested that TFs are the most limiting factor in developing universal treatment. Therefore, the identification and validation of new targets are, a continuous process in cancer drug discovery.

A lack of control over the expression or function of TFs leads to diseases like cancer. An estimated 300 transcription factors and their cofactors have been identified based on the analysis of cancer genes and are considered major contributors to cancer development.

The roles of TFs in the proliferation and differentiation of mammalian cells have been well established over the last few decades, and several hundred TFs have been identified. However, the failure rate of drug development is high when TFs are targeted.

NF-κB and p53, which play critical roles in cellular activities and tumorigenesis, were considered the two most promising target molecules in targeted drug discovery. NF-κB inhibitors have been developed to inhibit DNA binding activity, transactivation, and expression of this transcription factor. There are almost 800 inhibitors currently available. However, none of these inhibitors has shown clinical effectiveness. These observations lead to not considering them as priority targets.

ML and AI may shed some light on revisiting the strategies of TF-targeting based on current drug discovery knowledge.