A small-molecule inhibitor of PIM kinases as a potential treatment for urothelial carcinomas.

Abstract

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.

• Authors: Jason M Foulks, Kent J Carpenter, Bai Luo, Yong Xu, Anna Senina, Rebecca Nix, Ashley Chan, Adrianne Clifford, Marcus Wilkes, David Vollmer, Benjamin Brenning, Shannon Merx, Shuping Lai, Michael V McCullar, Koc-Kan Ho, Daniel J Albertson, Lee T Call, Jared J Bearss, Sheryl Tripp, Ting Liu, Bret J Stephens, Alexis Mollard, Steven L Warner, David J Bearss, Steven B Kanner
• Journal: Neoplasia (New York, N.Y.) (Neoplasia) Vol. 16 Issue 5 Pg. 403-12 (May 2014) ISSN: 1476-5586 [Electronic] United States
• PMID: 24953177 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014. Published by Elsevier Inc.

Chemical References

• Antineoplastic Agents
• Imidazoles
• MAS1 protein, human
• Oligopeptides
• Protein Kinase Inhibitors
• Proto-Oncogene Mas
• Pyridazines
• RNA, Small Interfering
• SGI 1776
• TP 3654
• Vasoactive Intestinal Peptide
• Proto-Oncogene Proteins c-pim-1
• proto-oncogene proteins pim

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Blotting, Western
• Carcinoma, Transitional Cell (enzymology)
• Female
• Humans
• Imidazoles (pharmacology)
• Male
• Mice
• Mice, Nude
• Multiplex Polymerase Chain Reaction
• Oligopeptides (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Mas
• Proto-Oncogene Proteins c-pim-1 (antagonists & inhibitors)
• Pyridazines (pharmacology)
• RNA, Small Interfering
• Rats
• Rats, Sprague-Dawley
• Reverse Transcriptase Polymerase Chain Reaction
• Transduction, Genetic
• Urinary Bladder Neoplasms (enzymology)
• Vasoactive Intestinal Peptide (pharmacology)
• Xenograft Model Antitumor Assays