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.
Public Health Relevance Statement: Narrative Prostate cancer (PCa) is the most common cancer of men and once spread it is incurable. The central premise of this application is that it is possible to develop highly potent and selective competitive inhibitors that regulate RNA decapping and thus stimulate the destruction of specific RNAs in tumor cells inhibiting tumor growth and invasion. The goal of this proposal is to develop a novel second generation small molecule drug that can be used in the clinic to regulate RNA destruction and thus block PCa growth.
Project Terms: Primary Protein Structure; protein sequence; Amino Acid Sequence; Animals; inhibitor; Arizona; Back; Dorsum; Binding Sites; Combining Site; Reactive Site; Biotechnology; Biotech; bone; Bone Marrow; Bone Marrow Reticuloendothelial System; Malignant Neoplasms; Cancers; Malignant Tumor; malignancy; neoplasm/cancer; Cell Adhesion; Cellular Adhesion; cell growth; Cellular Expansion; Cellular Growth; Cells; Cell Body; Pharmaceutical Chemistry; Medicinal Chemistry; Pharmaceutic Chemistry; Chemotaxis; Cessation of life; Death; Disease; Disorder; Drug resistance; drug resistant; resistance to Drug; resistant to Drug; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Epithelial Cells; Goals; Growth; Generalized Growth; Tissue Growth; ontogeny; Hormones; Endocrine Gland Secretion; Therapeutic Hormone; Human; Modern Man; Immunotherapy; Immune mediated therapy; Immunologically Directed Therapy; immune therapeutic approach; immune therapeutic interventions; immune therapeutic regimens; immune therapeutic strategy; immune therapy; immune-based therapies; immune-based treatments; immuno therapy; Lead; Pb element; heavy metal Pb; heavy metal lead; lymph nodes; Lymph Node Reticuloendothelial System; Lymph node proper; Lymphatic nodes; lymph gland; lymphnodes; men; Organoids; Patients; Drug Kinetics; Pharmacokinetics; Phosphorylation; Protein Phosphorylation; Phosphotransferases; Kinases; Phosphotransferase Gene; Transphosphorylases; Production; Prostate; Prostate Gland; Prostatic Gland; Protein Kinase; ATP-protein phosphotransferase; Kinase Family Gene; glycogen synthase a kinase; hydroxyalkyl protein kinase; phosphorylase b kinase kinase; Proteins; Publishing; Quality of life; QOL; RNA; Non-Polyadenylated RNA; RNA Gene Products; Ribonucleic Acid; Messenger RNA; mRNA; Serine; L-Serine; Signal Transduction; Cell Communication and Signaling; Cell Signaling; Intracellular Communication and Signaling; Signal Transduction Systems; Signaling; biological signal transduction; Structure-Activity Relationship; chemical structure function; structure function relationship; Testing; Universities; Protein-Serine-Threonine Kinases; Protein-Serine Kinase; Protein-Threonine Kinase; Serine Kinase; Serine-Threonine Kinases; Serine/Threonine Protein Kinase Gene; Threonine Kinase; cytokine; Generations; Enhancers; AKT; Akt protein; Protein Kinase B; RAC-PK protein; c-akt protein; proto-oncogene protein RAC; proto-oncogene protein akt; rac protein kinase; related to A and C-protein; Proto-Oncogene Proteins c-akt; Organ; improved; Phase; biologic; Biological; Chemicals; Hepatotoxic effect; Liver Toxicity; Toxic effect on liver cells; hepatic toxicity; hepatoxicity; Hepatotoxicity; analog; Collaborations; Therapeutic; Metabolic; tool; Malignant neoplasm of prostate; Malignant Tumor of the Prostate; Malignant prostatic tumor; Prostate CA; Prostate Cancer; Prostate malignancy; Prostatic Cancer; Investigation; Complex; Clinic; Techniques; Hormonal; Operative Surgical Procedures; Operative Procedures; Surgical; Surgical Interventions; Surgical Procedure; surgery; neoplastic cell; Tumor Cell; tumor growth; professor; synergism; nephrotoxicity; Nephrotoxic; kidney toxicity; Structure; Pharmacology and Toxicology; novel; Modality; Maximum Tolerated Dose; Maximal Tolerated Dose; Maximally Tolerated Dose; Regulation; Radiation; Modeling; Property; proto-oncogene protein pim; pim kinase; cancer therapy; Cancer Treatment; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; anti-cancer therapy; anticancer therapy; cancer-directed therapy; drug discovery; Molecular Interaction; Binding; RNA Degradation; Normal Cell; Tumor Invasion; Tumor Cell Invasion; preventing; prevent; small molecule; NCI-Designated Cancer Center; Protein Phosphorylation Inhibition; in vivo; Cancer Biology; Cancer Patient; Cell Mobility; Cellular Mobility; research clinical testing; Clinical Evaluation; Clinical Testing; clinical test; Invaded; Phosphorylation Inhibition; Scaffolding Protein; Development; developmental; designing; design; new approaches; novel approaches; novel strategy; novel strategies; anti-cancer activity; anticancer activity; Prostate CA therapy; prostate cancer treatment; Prostate Cancer therapy; migration; resistant; Resistance; chemotherapy; murine model; mouse model; tumor; prostate cancer cell line; clinical candidate; experiment; experimental research; experiments; experimental study; side effect; in silico; Compensation
