Small Molecules, Inhibitors of DNA-PK, Targeting DNA Repair, and Beyond

Abstract

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.

DNA-PKcs interference sensitizes colorectal cancer cells to a mTOR kinase inhibitor WAY-600

“…Recently, Ji et al, demonstrated that Ultra Violet (UV) radiation induced DNA-PKcs cytosol translocation and Sin1 association, which appeared required for mTORC2 activation and Akt phosphorylation (at Ser-473) [10]. Another explanation could be due to DNA-PKcs's ability to repair damaged DNA, which was observed in many cancer cells, serving as an important apoptosis resistance factor [11,31,32]. DNAPKcs inhibition, de-phosphorylation or depletion thus disrupts DNA repair process, and favors a pro-apoptosis outcome.…”

“…DNAPKcs is 460-kDa serine/threonine protein kinase, which belongs to phosphatidylinositol 3-kinase (PI3K)-like protein kinases (PIKK) family member [11,12]. Its main function is to dictate nonhomologous end joining (NHEJ) process thus repairing DNA double-strand breaks [11,12]. Studies have demonstrated DNA-PKcs overexpression/overactivation in CRC [13] and multiple other cancers, which regulates Akt-mTOR activation, and participates in oncogenic behaviors including cell survival, proliferation and radiation/chemotherapy resistance [9e11].…”

“…DNA-PK is a multipleeprotein complex composed of DNAdependent protein kinase catalytic subunit (DNA-PKcs), the heterodimer Ku70/80, XRCC4, and ligase IV, among others [11,12]. DNAPKcs is 460-kDa serine/threonine protein kinase, which belongs to phosphatidylinositol 3-kinase (PI3K)-like protein kinases (PIKK) family member [11,12]. Its main function is to dictate nonhomologous end joining (NHEJ) process thus repairing DNA double-strand breaks [11,12].…”

GBM radiosensitizers: dead in the water…or just the beginning?

“…Recent studies have suggested that these molecules may be sensitize the effects of alkylators (25) and radiotherapy (26) specifically in glioma. Small molecule inhibitors of canonical NHEJ proteins, such as DNA-PK, have been developed and are now being tested as radiosensitizers in clinical trials, although currently there are no studies specifically in GBM (27). One concern regarding the clinical utility of these agents is the lack of a therapeutic index, since normal tissue typically relies on canonical NHEJ repair to address DNA damage induced by radiotherapy (28).…”

RON Nuclear Translocation under Hypoxia Potentiates Chemoresistance to DNA Double-Strand Break–Inducing Anticancer Drugs

“…Recent studies report that activating NHEJ repair through the interaction of the DNA-PKcs with its partners induces chemoresistance in cancer cells (10) and that inhibiting it induces chemosensitization (11). Thus, targeting the NHEJ pathway is an innovative cancer therapy strategy (12)(13)(14).…”