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

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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.