Targeting transcription factors in cancer - from undruggable to reality

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Transcription factors regulate gene expression and are frequently mutated or dysregulated in cancer.
• Aberrant transcription factor activity drives cancer hallmarks like blocked differentiation and suppressed cell death.
• Mechanisms include direct genetic alterations (mutations, amplifications) and indirect effects via non-coding DNA.

Purpose of the Study:

• To review current and emerging strategies for targeting transcription factors as a therapeutic approach in cancer treatment.
• To highlight the potential of these novel approaches in overcoming therapeutic resistance and improving patient outcomes.

Main Methods:

• Review of preclinical and clinical studies on targeting transcription factor activity.
• Categorization of targeting strategies including protein-protein interaction inhibition, DNA binding inhibition, and modulation of protein degradation.
• Discussion of novel approaches such as PROTACs, cysteine reactive inhibitors, and targeting intrinsically disordered regions.

Main Results:

• Established methods like inhibiting protein-protein interactions and DNA binding are being refined.
• Emerging strategies offer new ways to modulate transcription factor activity and degradation.
• Combination therapies, such as with kinase inhibitors, are being explored to combat resistance.

Conclusions:

• Targeting transcription factors represents a promising avenue for novel cancer therapeutics.
• Innovations in drug development, including PROTACs and combination therapies, hold significant potential for future cancer treatment.
• These agents may offer unique properties to impact the management of various cancer types.