Many current chemotherapies function by damaging genomic DNA in rapidly dividing 
cells ultimately leading to cell death. This therapeutic approach differentially 
targets cancer cells that generally display rapid cell division compared to 
normal tissue cells. However, although these treatments are initially effective 
in arresting tumor growth and reducing tumor burden, resistance and disease 
progression eventually occur. A major mechanism underlying this resistance is 
increased levels of cellular DNA repair. Most cells have complex mechanisms in 
place to repair DNA damage that occurs due to environmental exposures or normal 
metabolic processes. These systems, initially overwhelmed when faced with 
chemotherapy induced DNA damage, become more efficient under constant selective 
pressure and as a result chemotherapies become less effective. Thus, inhibiting 
DNA repair pathways using target specific small molecule inhibitors may overcome 
cellular resistance to DNA damaging chemotherapies. Non-homologous end joining a 
major mechanism for the repair of double-strand breaks (DSB) in DNA is regulated 
in part by the serine/threonine kinase, DNA dependent protein kinase (DNA-PK). 
The DNA-PK holoenzyme acts as a scaffold protein tethering broken DNA ends and 
recruiting other repair molecules. It also has enzymatic activity that may be 
involved in DNA damage signaling. Because of its' central role in repair of 
DSBs, DNA-PK has been the focus of a number of small molecule studies. In these 
studies specific DNA-PK inhibitors have shown efficacy in synergizing 
chemotherapies in vitro. However, compounds currently known to specifically 
inhibit DNA-PK are limited by poor pharmacokinetics: these compounds have poor 
solubility and have high metabolic lability in vivo leading to short serum 
half-lives. Future improvement in DNA-PK inhibition will likely be achieved by 
designing new molecules based on the recently reported crystallographic 
structure of DNA-PK. Computer based drug design will not only assist in 
identifying novel functional moieties to replace the metabolically labile 
morpholino group but will also facilitate the design of molecules to target the 
DNA-PKcs/Ku80 interface or one of the autophosphorylation sites.