Disruption of Protein–DNA Interactions: An Opportunity for Cancer Chemotherapy

Abstract

The use of inhibitors, both natural and synthetic has been a mainstay in the biochemical analysis of cellular pathways from glycolysis, the TCA cycle and the electron transport chain to DNA replication, cell signaling and apoptosis. With advents in screening technology, robotics and combinatorial chemistry, the field of chemical genetics was born. The development and use of small molecule inhibitors (SMIs) to modulate the activities of proteins has provided a wealth of knowledge on a variety of pathways and enhanced drug development targeting novel proteins and activities. The effectiveness of targeting enzymesubstrate interactions is well established and only more recently have protein-protein interactions been effectively targeted with SMIs (Saha et al., 2010; Huang et al., 2008; De et al., 2009; Ballatore et al., 2010; Yang et al., 2010; Weber, 2010). While targeting protein-DNA interactions has been considered by some to be “undrugable interactions” we and others have succeeded in developing SMIs capable of inhibiting these often complex interactions. The ability to develop inhibitors of protein-DNA complex formation capable of in vivo activity opens up an entire new class of targetable molecule interactions for potential therapeutic benefit. One could envision inhibiting proteins involved in transcription in addition to DNA replication, DNA repair and recombination. This review will summarize the recent successes in targeting protein-DNA interactions and draw the distinction between those agents that inhibit these interactions directly versus those that reduce protein-DNA interactions via indirect mechanisms. We also highlight the development of DNA repair inhibitors focusing on the clinical utility of targeting DNA repair for cancer therapy.