Targeting the DNA repair enzyme apurinic/apyrimidinic endonuclease (APE1) to treat cancer

细胞通过上调其DNA损伤反应(DDR)通路来应对DNA损伤的增加。 复制应激、细胞新陈代谢增加和接触化疗药物都会导致 癌细胞的DNA损伤水平升高。碱基切除修复(BER)途径纠正损伤 通过几种酶的作用而产生的单个DNA碱基，包括中心参与者脱嘌呤/脱嘧啶 核酸内切酶1(APE1)。多项研究表明，APE1水平升高与 增强人类肿瘤细胞的生长、迁移和耐药性，并降低患者的存活率 总体而言。到目前为止，APE1已经与20多种人类癌症有关，使这种酶成为一个有吸引力的靶点 用于未来抗癌治疗的发展。目前还没有抑制DNA修复活性的药物 APE1在临床上。一种新开发的基于结晶学的高通量片段筛查导致了 APE1酶切位点上化学碎片的高分辨晶体结构。这些是 首次实验APE1与类药物分子结合的3D结构，从而解决了 开发抑制剂的途径。在这项第一阶段的研究中，我们建议将这些片段打入到抑制剂中 通过计算和药物化学、结构生物学和生物化学的结合 和生物物理化验。完成这项第一阶段的提案将使第二阶段的申请能够扩大 并优化先导化合物的类药物性能。

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.