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

前列腺癌（PCa）是男性最常见的杀手，每年有超过34，000人死亡。如果PCa未治愈 通过最初的确定性手术和/或放射并扩散到淋巴结、骨骼或其他器官 是没有疗效的激素阻断、化疗和免疫疗法具有显著的副作用， 影响患者的生活质量。因此，对于那些标准治疗失败的人，需要新的治疗方法。的 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 癌症治疗初步结果表明，可以产生调节RNA的小分子， 脱帽并因此增强RNA破坏。实验表明，支架蛋白需要 RNA去帽增强子3（EDC 3）被Pim 1和3丝氨酸蛋白严重磷酸化 磷酸化抑制了PCa中的激酶，并且这种磷酸化抑制了其调节脱帽的能力。阻断EDC 3的能力 结合Pim 1和3逆转了这种抑制作用，并导致特定的RNA组的破坏，RNA是细胞生长的调节因子。 粘附、细胞因子产生和细胞移动性。用新的小分子抑制EDC 3磷酸化， VBT-34阻止PCa生长和入侵。这种第一代化合物是在一次筛选中鉴定出来的， 包括高水平的ATP，从而允许鉴定潜在的变构抑制剂。Pim建模1 和3的结构表明，目前的铅化合物VBT-34适合在一个新确定的口袋， Pim 1和3激酶。没有明显的证据表明EDC 3的代偿性磷酸化，特别是通过AKT磷酸化。 在PCa中高度活化的激酶已经被鉴定。本申请的具体目的是 改善VBT-34的药物样性质：1-设计、合成和测试VBT类似物，以i）增加 该化合物抑制EDC 3：Pim 1/3复合物形成的效力 先导化合物的理化和药代动力学性质。新型VBT类似物将被优化 通过计算机模拟和构效关系（SAR）研究指导的迭代研究。2- 采用动物肿瘤模型测定先导化合物的最大耐受剂量和抗肿瘤疗效。 研究新合成的先导化合物是否抑制PCa、生长、侵袭和RNA 降解将满足化合物推进至每个试验水平的严格通过/不通过标准。这一努力 将由安德鲁博士领导的Vortex生物技术公司进行。卡夫，一个过去的董事两个 与亚利桑那大学中心联合主任王伟博士合作的NCI指定癌症中心 药物发现和药理学和毒理学教授。这个小组将使用最先进的药物 开发第二代抑制剂的发现工具，可以过渡到临床。调控 因此，刺激特异性RNA降解是抑制癌症的一流方法 入侵和生长。该团队具有合成、评估和推进化合物进入阶段的专业知识 II应用和人体临床试验。

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.