A Small-Molecule Inhibitor of PIM Kinases as a Potential Treatment for Urothelial Carcinomas
| Autor: | David J. Bearss, Jared Bearss, Lee T. Call, Alexis Mollard, Shuping Lai, Steven L. Warner, Dan Albertson, Shannon Merx, Ashley Chan, Michael V. McCullar, Yong Xu, Rebecca N. Nix, Anna Senina, Marcus Wilkes, Ting Liu, Bret Stephens, Jason M. Foulks, Steven B. Kanner, David Vollmer, Kent J. Carpenter, Adrianne Clifford, Benjamin Brenning, Koc Kan Ho, Bai Luo, Sheryl R. Tripp |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Cancer Research Blotting Western Bcl-2-associated death promoter Mice Nude Antineoplastic Agents Proto-Oncogene Mas lcsh:RC254-282 Article Rats Sprague-Dawley Mice Proto-Oncogene Proteins c-pim-1 Transduction Genetic hemic and lymphatic diseases medicine Animals Humans RNA Small Interfering Protein Kinase Inhibitors AML acute myeloid leukemia Carcinoma Transitional Cell biology BAD Bcl-2 associated death promoter Cell growth Kinase Reverse Transcriptase Polymerase Chain Reaction Imidazoles hERG human ether-à-go-go-related gene Cell cycle medicine.disease lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Xenograft Model Antitumor Assays Rats Pyridazines STAT signal transducer and activator of transcription Leukemia Urinary Bladder Neoplasms Cancer cell Fms-Like Tyrosine Kinase 3 biology.protein Cancer research STAT protein Female FLT3 fms-like tyrosine kinase 3 PIM proviral integration site for moloney murine leukemia virus Multiplex Polymerase Chain Reaction Oligopeptides Vasoactive Intestinal Peptide |
| Zdroj: | Neoplasia: An International Journal for Oncology Research, Vol 16, Iss 5, Pp 403-412 (2014) Neoplasia (New York, N.Y.) |
| ISSN: | 1476-5586 |
| DOI: | 10.1016/j.neo.2014.05.004 |
| Popis: | The proto-oncogene proviral integration site for moloney murine leukemia virus (PIM) kinases (PIM-1, PIM-2, and PIM-3) are serine/threonine kinases that are involved in a number of signaling pathways important to cancer cells. PIM kinases act in downstream effector functions as inhibitors of apoptosis and as positive regulators of G1-S phase progression through the cell cycle. PIM kinases are upregulated in multiple cancer indications, including lymphoma, leukemia, multiple myeloma, and prostate, gastric, and head and neck cancers. Overexpression of one or more PIM family members in patient tumors frequently correlates with poor prognosis. The aim of this investigation was to evaluate PIM expression in low- and high-grade urothelial carcinoma and to assess the role PIM function in disease progression and their potential to serve as molecular targets for therapy. One hundred thirty-seven cases of urothelial carcinoma were included in this study of surgical biopsy and resection specimens. High levels of expression of all three PIM family members were observed in both noninvasive and invasive urothelial carcinomas. The second-generation PIM inhibitor, TP-3654, displays submicromolar activity in pharmacodynamic biomarker modulation, cell proliferation studies, and colony formation assays using the UM-UC-3 bladder cancer cell line. TP-3654 displays favorable human ether-à-go-go-related gene and cytochrome P450 inhibition profiles compared with the first-generation PIM inhibitor, SGI-1776, and exhibits oral bioavailability. In vivo xenograft studies using a bladder cancer cell line show that PIM kinase inhibition can reduce tumor growth, suggesting that PIM kinase inhibitors may be active in human urothelial carcinomas. |
| Databáze: | OpenAIRE |
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