PHARMACOLOGICAL MODULATION OF POLY(ADP-RIBOSE) METABOLISM

多聚（ADP-核糖）代谢的药理学调节

• 批准号: 9333793
• 负责人: Darin E. Jones
• 金额: $ 33.17万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-07 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9333793
• 关键词: Accounting; Active Sites; Adenosine Diphosphate Ribose; Agonist; Apoptosis; BRCA1 gene; BRCA2 gene; Binding; Binding Sites; Biochemical; Biological Assay; Breast Cancer Treatment; C-terminal; Cell Death; Cell Line; Cells; Chemicals; Chemotherapy-Oncologic Procedure; Clinical; Collaborations; Complement; Complex; Core Facility; Cultured Cells; Cyclic ADP-Ribose; DNA Damage; DNA Repair; DNA Structure; Data; Defect; Development; Disease; Dose; Dose-Limiting; Enzymes; Gel; Genetic; Genotype; Goals; Health; Human; Hydrolysis; Immunodeficient Mouse; In Vitro; Lead; Libraries; Link; Malignant Neoplasms; Malignant neoplasm of ovary; Mammary Neoplasms; Metabolism; Minority; Modality; Mus; Mutation; Orthologous Gene; Outcome; Oxidative Stress; Patients; Pharmaceutical Preparations; Phenocopy; Physiological; Poly Adenosine Diphosphate Ribose; Poly(ADP-ribose) Polymerases; Post-Translational Protein Processing; Process; Proteins; Radiation; Reagent; Resistance; Role; Serum; Site; Stress; Structure; Testing; Therapeutic; Toxic effect; Transformed Cell Line; Tyrosine; Xenograft Model; acute toxicity; analog; base; cancer cell; cancer therapy; chemical function; chemical synthesis; chemosensitizing agent; chemotherapy; design; high throughput screening; improved; in vitro testing; in vivo; inhibitor/antagonist; killings; knock-down; malignant breast neoplasm; member; metabolomics; methylxanthine; nanomolar; new therapeutic target; ovarian neoplasm; patch clamp; poly ADP-ribose glycohydrolase; preclinical evaluation; preclinical trial; quantitative imaging; research study; response; screening; signal processing; small molecule; small molecule libraries; success; sulfated glycoprotein 2; targeted cancer therapy; targeted treatment; therapy resistant; tumor; tumor growth

 DESCRIPTION (provided by applicant): Molecularly-targeted cancer therapies have revolutionized the treatment of this heterogeneous and increasingly prevalent disease. Genetic instability is a hallmark of many cancers that generates mutations to support uncontrolled tumor growth and resistance to chemotherapies. The underlying DNA repair defects in these tumors can be exploited in tumor-selective therapies that block critical remaining DNA repair functions to trigger catastrophic damage and cell death. This idea is borne out by the clinical successes of inhibitors of poly(ADP-ribose) polymerase 1 (PARP1) to treat breast and ovarian cancers with mutations in BRCA1 or BRCA2. However, these BRCA-deficient tumors account for a minority of cancers so it is important to identify other physiological defects of tumors that are synthetically lethal in combination with molecularly targeted therapies. Additionally, the current PARP inhibitors suffer from dose-limiting toxicities, which may result from off-target effects on other members of the large PARP superfamily. As an alternative to PARP inhibitors, we used high-throughput screening to identify selective inhibitors of the human poly(ADP-ribose) glycohydrolase PARG. PARG is a monogenic enzyme that removes the poly(ADP-ribose) posttranslational modification of proteins modified by PARP1. A genetic knockdown of PARG sensitizes cancer cells to DNA damaging agents and radiation and phenocopies the tumor-specific killing effects of PARP1 enzymatic inhibitors in BRCA- deficient cancer cells. In this application, we propose experiments to improve the potency and selectivity of small molecule PARG inhibitors through structure-guided chemical synthesis and testing in vitro, and to advance selected compounds to preclinical trials of tumor killing activity in cultured cells and xenograft models of breast cancer. We will also investigate the role of the nonselective Ca2+ channel TRPM2 in PARP1- dependent cell death. The TRPM2 channel is activated by the PARG metabolite ADP-ribose. We will develop small molecule modulators of the ADP-ribose responsive gating domain of TRPM2 by high throughput screening and structure-based optimization of compound potency. Our studies will advance understanding of the relevant signaling processes and outcomes of chemotherapies that target DNA damage.

 描述（由适用提供）：分子靶向癌症疗法已彻底改变了这种异质性和日益普遍疾病的治疗。遗传不稳定性是许多癌症的标志，它们产生突变以支持不受控制的肿瘤生长和对化学疗法的抗性。可以在肿瘤选择疗法中探索这些肿瘤中的基本DNA修复缺陷，以阻断关键剩余的DNA修复功能以触发灾难性损伤和细胞死亡。这个想法是由聚（ADP-核糖）聚合酶1（PARP1）抑制剂的临床成功诞生的，可以治疗BRCA1或BRCA2突变的乳腺癌和卵巢癌。但是，这些BRCA缺陷瘤造成了少数癌症，因此重要的是要鉴定出合成致死的肿瘤与分子靶向疗法的其他肿瘤的其他物理缺陷。此外，当前的PARP抑制剂患有限制剂量的毒性，这可能是由于对大型PARP超家族其他成员的非目标影响而产生的。作为PARP抑制剂的替代方法，我们使用了高通量筛选来识别人类聚（ADP-核糖）甘氨酸糖酶PARG的选择性抑制剂。 PARG是一种单基因酶，可去除通过PARP1修饰的蛋白质后的聚（ADP-核糖）修饰。 PARG的遗传敲低使癌细胞对DNA损伤剂和辐射和表型敏感，而表情是PARP1酶抑制剂在BRCA降低的癌细胞中的肿瘤特异性杀伤作用。在此应用中，我们提出了实验，以通过结构引导的化学合成和体外测试来提高小分子PARG抑制剂的效力和选择性，并将所选化合物推向培养的细胞中肿瘤杀死活性和乳腺癌异种移植模型的临床前试验。我们还将研究非选择性Ca2+通道TRPM2在PARP1依赖性细胞死亡中的作用。 TRPM2通道被PARG代谢物ADP-核糖激活。我们将通过高吞吐量筛选和基于结构的复合效力的优化来开发TRPM2的ADP-核糖反应性门控域的小分子调节剂。我们的研究将进一步了解针对DNA损伤的化学疗法的相关信号过程和结果。