A complex task? Direct modulation of transcription factors with small molecules

Transcription factors with aberrant activity in disease are promising yet untested targets for therapeutic development, particularly in oncology. Directly inhibiting or activating the function of a transcription factor requires specific disruption or recruitment of protein–protein or protein–DNA interactions. The discovery or design of small molecules that specifically modulate these interactions has thus far proven to be a significant challenge and the protein class is often perceived to be ‘undruggable.’ This review will summarize recent progress in the development of small-molecule probes of transcription factors and provide evidence to challenge the notion that this important protein class is chemically intractable.