Cells respond to increases in DNA damage by upregulating their DNA damage response (DDR) pathways. Replicative stress, increased cellular metabolism and exposure to chemotherapeutic agents all contribute to elevated levels of DNA damage in cancer cells. The base excision repair (BER) pathway corrects damage to single DNA bases through the action of several enzymes, including the central participant, apurinic/apyrimidinic endonuclease 1 (APE1). Several studies have demonstrated an association between increased APE1 levels and enhanced growth, migration, and drug resistance in human tumor cells, as well as with decreased patient survival overall. To date, APE1 has been implicated in over 20 human cancers, making this enzyme an attractive target for the development of future anticancer therapies. There are currently no inhibitors of the DNA repair activity of APE1 in the clinic. A newly developed high-throughput crystallography-based fragment screen has resulted in high resolution crystal structures of chemical fragments bound to the endonuclease site of APE1. These are the first experimental 3D structures of APE1 bound to drug-like molecules, thereby resolving a primary bottleneck in the path to inhibitor development. In this Phase I study, we propose to elaborate these fragment hits into inhibitors of APE1 through a combination of computational and medicinal chemistry, structural biology, and biochemical and biophysical assays. Completion of this Phase I proposal will enable a Phase II application to expand the SAR and optimize the drug-like properties of the lead compound.
Tumors often overexpress DNA repair enzymes contributing to disease progression and resistance to available therapies. We are developing inhibitors against one enzyme involved in DNA repair that has been found overexpressed in many cancers. Inhibitors may be effective as single agents but could also be used to make existing therapies more effective.
