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）是最常见的男性杀手，每年死亡超过34,000人。如果未治愈PCA 通过初始的明确手术和/或辐射，并扩散到淋巴结，骨骼或其他器官当前疗法无法治愈。激素阻断，化疗和免疫疗法具有显着的副作用，影响患者的生活质量。那些失败的标准疗法需要新颖的治疗方法。这该提案的目标是开发一个新的，一类小型的小分子调节剂RNA破坏作为PCA 癌症治疗。初步结果表明可以创建小分子来调节RNA decap缩，从而增强RNA破坏。实验表明，脚手架蛋白需要 Decapping 3（EDC3）的RNA Decapping增强子被PIM 1和3串行蛋白磷酸化 PCA中的激酶，这种磷酸化抑制了其调节脱皮的能力。阻止EDC3的能力结合PIM1和3逆转了这种抑制作用，并导致破坏特定的RNA集合，细胞的调节剂粘附，细胞因子产生和细胞迁移率。用一种新型的小分子抑制EDC3磷酸化， VBT-34阻止了PCA的生长和入侵。在屏幕上确定了这种化合物的第一代包括高水平的ATP，因此可以鉴定潜在的变构抑制剂。建模PIM1 3结构表明，当前的铅化合物VBT-34适合在新近确定的口袋中 PIM 1和3激酶。没有明显的补偿性EDC3磷酸化证据，特别是AKT 在PCA中高度激活的激酶已被鉴定出来。此应用的具体目的是改善VBT-34的药物样特性：1-设计，合成和测试VBT类似物i）增加抑制EDC3的化合物的效力：PIM1/3复合物形成ii）铅化合物的物理化学和药代动力学特性。新颖的VBT类似物将被优化由迭代研究以计算机建模和结构活性关系（SAR）研究为指导。 2- 使用动物肿瘤模型确定铅化合物最大耐受剂量和抗肿瘤效率。研究新合成的铅化合物是否抑制了PCA，生长，侵袭和RNA是否抑制降解。严格的GO/NO GO标准将满足复合进步到每个测试级别的问题。这项努力将由Vortex Biotechnology Corporation执行的Andrew S. Kraft博士， NCI指定的癌症中心与亚利桑那大学中心的Wei Wang博士合作主任合作用于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以过渡到诊所的第二代抑制剂的发现工具。调节 decapping，因此刺激特定的RNA降解是一种抑制癌症的第一类方法入侵和成长。该团队具有综合，评估和提高化合物的专业知识 II应用和人类临床测试。