There is a growing body of evidence that implicates the protein kinase Pim-1 as a major driver of prostate cancer progression, and perhaps response to chemotherapy. Pim-1 is overexpressed in early prostate intraepithelial neoplasia and metastatic prostate cancer, and its levels predict response to therapy. Pim-1-overexpressing mouse prostate stem cells demonstrate abnormal growth in 3-D collagen cultures, and develop into PIN when placed under the renal capsule. In Rbnull stem cells, Pim-1 overexpression induces frank neoplasia when grown in the renal capsule model. Pim-1 modulates signaling through the mTOR pathway, providing additional opportunities for targeted cancer therapy. Therefore, the goal of this program is to develop unique inhibitors of Pim-1 that will function, with or without a TOR protein kinase inhibitor such as rapamycin, to treat prostate cancer. We have identified a new chemotype that inhibits Pim-1 protein kinase activity both in vitro and in intact cells. In this Phase I STTR project, we will address the feasibility of developing new Pim-1 inhibitors with anticancer activity through the following Specific Aims: 1) To optimize the Pim-1 inhibitors using medicinal and computational chemistry; 2) To evaluate the effects of the new compounds on Pim-1 in vitro and in prostate cancer cells; and 3) To evaluate the anticancer efficacy of Pim-1 inhibitors in vivo. These studies provide an efficient process for the synthesis and evaluation of new inhibitors of an emerging target for prostate cancer chemotherapy. Completion of these Specific Aims will provide a clear demonstration of the feasibility of using Pim-1 inhibitors as anticancer agents, and identify the drug candidate for further development in a Phase II STTR project.
Public Health Relevance: The Pim protein kinases are critical enzymes involved in the pathogenesis of prostate cancer. In this project, we have developed methods for synthesizing and testing new inhibitors of Pim kinases. Continued development of these compounds is necessary to provide important new drugs for the treatment of prostate cancer.,
Public Health Relevance Statement:, Project Narrative The Pim protein kinases are critical enzymes involved in the pathogenesis of prostate cancer. In this project, we have developed methods for synthesizing and testing new inhibitors of Pim kinases. Continued development of these compounds is necessary to provide important new drugs for the treatment of prostate cancer.,
Project Terms:, 3-D; 3-Dimensional; ATP-protein phosphotransferase; Address; Anti-Cancer Agents; Anti-Tumor Agents; Anti-Tumor Drugs; Antineoplastic Agents; Antineoplastic Drugs; Antineoplastics; Antiproliferative Agents; Antiproliferative Drugs; Apoptosis; Apoptosis Pathway; Attenuated; Cancer Center; Cancer Drug; Cancer Genes; Cancer Screening for Patients; Cancer Treatment; Cancer of Prostate; Cancer-Promoting Gene; Cancers; Cell Communication and Signaling; Cell Death, Programmed; Cell Growth in Number; Cell Multiplication; Cell Proliferation; Cell Signaling; Cell model; Cells; Cellular Proliferation; Cellular model; Chemistry, Pharmaceutical; Chemotherapeutic Agents, Neoplastic Disease; Chemotherapy Protocol; Chemotherapy Regimen; Chemotherapy, Cancer, General; Chemotherapy-Oncologic Procedure; Clinical Evaluation; Clinical Testing; Collagen; Combination Chemotherapy Regimen; Development; Disease; Disorder; Dose; Drug Kinetics; Drugs; Enzymes; Epithelial Dysplasia; Evaluation; FK506 Binding Protein 12-Rapamycin Associated Protein 1; FK506 Binding Protein 12-Rapamycin Associated Protein 2; FK506 binding protein 12-rapamycin associated protein 1, human; FKBP-Rapamycin Associated Protein; FKBP-rapamycin associated protein, human; FKBP12 Rapamycin Complex Associated Protein 1; FRAP1 protein, human; Fibrous capsule of kidney; Generalized Growth; Genital System, Male, Prostate; Goals; Growth; Human Prostate; Human Prostate Gland; In Vitro; Intracellular Communication and Signaling; Intraepithelial Neoplasia; Intraepithelial Neoplasms; Isoenzymes; Isozymes; Lead; Lymphocytic Neoplasm; Lymphocytic Tumor; Lymphocytic and Plasma Cell Neoplasm; Lymphocytic and Plasma Cell Tumour; Lymphocytic and Plasmacytic Neoplasm; Lymphoid Tumor; Lymphoid and Plasma Cell Tumour; Lymphoid and Plasmacytic Neoplasm; Lymphoid and Plasmacytic Tumour; Malignant Cell; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; Malignant Neoplasms; Malignant Tumor; Malignant Tumor of the Prostate; Malignant neoplasm of prostate; Malignant prostatic tumor; Mammals, Mice; Mediating; Medical; Medication; Medicinal Chemistry; Metastatic Prostate Cancer; Methods; Mice; Modeling; Mother Cells; Murine; Mus; Neoplasms; Oncogenes; Oncogenic; Pathogenesis; Pathway interactions; Pb element; Pharmaceutic Chemistry; Pharmaceutic Preparations; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacokinetics; Phase; Phosphorylation; Process; Progenitor Cells; Programs (PT); Programs [Publication Type]; Property; Property, LOINC Axis 2; Prostate; Prostate CA; Prostate Cancer; Prostate Carcinoma Metastatic; Prostate Gland; Prostatic Cancer; Prostatic Gland; Protein Kinase; Protein Kinase Inhibitors; Protein Phosphorylation; Quimioterapia; RAFT1 protein, human; RAPT1 protein, human; Rapamune; Rapamycin; Rapamycin Target Protein; Renal Capsule; Role; STTR; Screening for cancer; Series; Signal Transduction; Signal Transduction Systems; Signaling; Sirolimus; Small Business Technology Transfer Research; South Carolina; Stem cells; Structure-Activity Relationship; Testing; Tissue Growth; Transforming Genes; Treatment Efficacy; Tumor Cell; Tumor-Specific Treatment Agents; Tumors; Universities; anticancer activity; anticancer agent; anticancer drug; anticancer therapy; biological signal transduction; cancer cell; cancer chemotherapy; cancer progression; cancer therapy; chemical structure function; chemotherapy; clinical test; computational chemistry; disease/disorder; drug candidate; drug/agent; early cancer detection; experience; experiment; experimental research; experimental study; glycogen synthase a kinase; heavy metal Pb; heavy metal lead; human FRAP1 protein; hydroxyalkyl protein kinase; in vitro activity; in vivo; inhibitor; inhibitor/antagonist; lymphoid neoplasm; mTOR; malignancy; mouse model; neoplasia; neoplasm progression; neoplasm/cancer; neoplastic cell; neoplastic growth; neoplastic progression; novel; ontogeny; overexpression; pathway; phosphorylase b kinase kinase; pim kinase; programs; protein kinase inhibitor; proto-oncogene protein pim; public health relevance; rapamycin and FKBP12 target 1 protein, human; research clinical testing; research study; response; secondary outcome; small molecule; small molecule libraries; social role; structure function relationship; therapeutic efficacy; therapeutically effective; tumor; tumor growth; tumor progression
