Regulation of RNA Decapping and Degradation: A novel approach to prostate cancer therapy

RNA 脱帽和降解的调控：前列腺癌治疗的新方法

基本信息

批准号：
10758110
负责人：
Andrew S Kraft
金额：
$ 39.72万
依托单位：
VORTEX BIOTECHNOLOGY CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10758110
关键词：
Amino Acid Sequence Animals Arizona Back Binding Binding Sites Biological Biotechnology Bone Marrow Cancer Biology Cancer Patient Cell Adhesion Cell Mobility Cells Cessation of life Chemicals Chemotaxis Clinic Collaborations Compensation Complex Development Disease Drug Kinetics Drug resistance Enhancers Epithelial Cells Generations Goals Growth Hepatotoxicity Hormonal Hormones Human Immunotherapy Invaded Investigation Lead Malignant Neoplasms Malignant neoplasm of prostate Maximum Tolerated Dose Messenger RNA Metabolic Modality Modeling NCI-Designated Cancer Center Normal Cell Operative Surgical Procedures Organ Organoids Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology and Toxicology Phase Phosphorylation Phosphorylation Inhibition Phosphotransferases Production Property Prostate Prostate Cancer therapy Protein Kinase Protein Phosphorylation Inhibition Protein-Serine-Threonine Kinases Proteins Proto-Oncogene Proteins c-akt Publishing Quality of life RNA RNA Degradation Radiation Regulation Resistance Scaffolding Protein Serine Signal Transduction Structure Structure-Activity Relationship Techniques Testing Therapeutic Tumor Cell Invasion Universities analog anticancer activity bone cancer therapy cell growth chemotherapy clinical candidate cytokine design drug discovery experimental study improved in silico in vivo inhibitor lymph nodes men migration mouse model neoplastic cell nephrotoxicity novel novel strategies prevent professor prostate cancer cell line proto-oncogene protein pim research clinical testing side effect small molecule synergism tool tumor tumor growth

项目摘要

Prostate cancer (PCa) is the most frequent killer of men with over 34,000 deaths per year. If PCa is not cured by initial definitive surgery and/or radiation and spreads to lymph nodes, bones, or other organs current therapies are not curative. Hormone blockade, chemotherapy, and immunotherapy have significant side effects that impact the patient’s quality of life. Thus, novel treatments are needed for those who fail standard therapy. The goal of this proposal is to develop a new, first-in-class small molecule regulator of RNA destruction as a PCa cancer treatment. Preliminary results demonstrate that small molecules can be created which regulate RNA decapping and thus enhance RNA destruction. Experiments demonstrate that the scaffold protein needed for RNA decapping Enhancer of Decapping 3 (EDC3) is heavily phosphorylated by the Pim 1 and 3 serine protein kinases in PCa, and this phosphorylation inhibits its ability to regulate decapping. Blocking the ability of EDC3 to bind Pim1 and 3 reverses this inhibition and leads to the destruction of specific set of RNAs, regulators of cell adhesion, cytokine production, and cell mobility. Inhibiting EDC3 phosphorylation with a novel small molecule, VBT-34 blocks PCa growth and invasion. This first-generation of compounds was identified in a screen that included high levels of ATP thus allowing the identification of potential allosteric inhibitors. Modeling the Pim1 and 3 structure demonstrates that the current lead compound VBT-34 fits into a newly identified pocket in the Pim 1 and 3 kinase. No significant evidence of compensatory EDC3 phosphorylation, particularly by the AKT kinase, which is highly activated in PCa, has been identified. The Specific Aims of this application are to improve the drug-like properties of VBT-34: 1- Designing, synthesizing, and testing VBT analogs to i) increase the potency of the compound for the inhibition of EDC3:Pim1/3 complex formation ii) improve the physicochemical and pharmacokinetic properties of the lead compound. The novel VBT analogs will be optimized by iterative studies guided by in silico modeling and structure-activity relationship (SAR) investigation. 2- Determine lead compound maximum tolerated dose and antitumor efficacy using animal tumor models. Investigate whether the newly synthesized lead compound inhibit(s) PCa, growth, invasion, and RNA degradation. Strict go/no go criteria for compound advancement to each level of testing will be met. This effort will be carried out by Vortex Biotechnology Corporation headed by Dr. Andrew S. Kraft, a past Director of two NCI-designated Cancer Centers collaborating with Dr. Wei Wang Co-Director of the University of Arizona Center for Drug Discovery and Professor of Pharmacology and Toxicology. This team will use state-of-the-art drug discovery tools to develop second generation inhibitors that can be transitioned into the clinic. Regulation of decapping, and thus the stimulation of specific RNA degradation is a first-in-class approach to inhibiting cancer invasion and growth. This team has the expertise to synthesize, evaluate, and advance compounds into a phase II application and human clinical testing.

前列腺癌 (PCa) 是男性最常见的杀手，如果 PCa 未治愈，每年有超过 34,000 人死亡。通过最初的确定性手术和/或放射治疗，并扩散到淋巴结、骨骼或其他器官。激素阻断、化疗和免疫疗法具有显着的副作用。因此，对于标准治疗失败的患者来说，需要新的治疗方法。该提案的目标是开发一种新的、一流的 RNA 破坏小分子调节剂，作为 PCa 初步结果表明可以产生调节 RNA 的小分子。实验证明支架蛋白需要脱帽，从而增强RNA破坏。 RNA 脱帽增强剂 of Decapping 3 (EDC3) 被 Pim 1 和 3 丝氨酸蛋白严重磷酸化 PCa 中的激酶，这种磷酸化会抑制其调节脱帽的能力，从而阻断 EDC3 的能力。结合 Pim1 和 3 可逆转这种抑制并导致特定组 RNA（细胞调节因子）的破坏用新型小分子抑制 EDC3 磷酸化， VBT-34 可以阻断 PCa 的生长和侵袭，这是在筛选中鉴定出的第一代化合物。包括高水平的 ATP，从而可以识别潜在的变构抑制剂。和 3 结构表明当前的先导化合物 VBT-34 适合放入新识别的口袋中 Pim 1 和 3 激酶没有明显证据表明补偿性 EDC3 磷酸化，特别是 AKT 磷酸化。已确定在 PCa 中高度激活的激酶。改善 VBT-34 的类药特性： 1- 设计、合成和测试 VBT 类似物 i) 增加该化合物抑制 EDC3:Pim1/3 复合物形成的效力 ii) 提高先导化合物的理化和药代动力学特性将得到优化。通过计算机建模和结构-活性关系 (SAR) 研究 2- 指导下的迭代研究。使用动物肿瘤模型确定先导化合物最大耐受剂量和抗肿瘤功效。研究新合成的先导化合物是否抑制 PCa、生长、侵袭和 RNA 将满足化合物进步到每个测试级别的严格的通过/不通过标准。将由 Vortex Biotechnology Corporation 进行，该公司由 Andrew S. Kraft 博士领导，他是两家公司的前任董事 NCI 指定癌症中心与亚利桑那大学中心联合主任 Wei Wang 博士合作药物发现和药理学和毒理学教授该团队将使用最先进的药物。开发可转化为临床监管的第二代抑制剂的发现工具。脱帽，因此刺激特定 RNA 降解是抑制癌症的一流方法该团队拥有合成、评估和推进化合物进入阶段的专业知识。 II 应用及人体临床试验。