title: 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: Astex Pharmaceuticals, Inc, Salt Lake City, UT.
authors: Jason M
authors: JM
authors: Foulks
authors: Tolero Pharmaceuticals, Inc, Lehi, UT.
authors: Kent J
authors: KJ
authors: Carpenter
authors: Astex Pharmaceuticals, Inc, Salt Lake City, UT.
authors: Bai
authors: B
authors: Luo
authors: Astex Pharmaceuticals, Inc, Salt Lake City, UT.
authors: Yong
authors: Y
authors: Xu
authors: Astex Pharmaceuticals, Inc, Salt Lake City, UT.
authors: Anna
authors: A
authors: Senina
authors: Astex Pharmaceuticals, Inc, Salt Lake City, UT.
authors: Rebecca
authors: R
authors: Nix
authors: Astex Pharmaceuticals, Inc, Salt Lake City, UT.
authors: Ashley
authors: A
authors: Chan
authors: Astex Pharmaceuticals, Inc, Salt Lake City, UT.
authors: Adrianne
authors: A
authors: Clifford
authors: Astex Pharmaceuticals, Inc, Salt Lake City, UT.
authors: Marcus
authors: M
authors: Wilkes
authors: Astex Pharmaceuticals, Inc, Salt Lake City, UT.
authors: David
authors: D
authors: Vollmer
authors: Astex Pharmaceuticals, Inc, Salt Lake City, UT.
authors: Benjamin
authors: B
authors: Brenning
authors: Astex Pharmaceuticals, Inc, Salt Lake City, UT.
authors: Shannon
authors: S
authors: Merx
authors: Astex Pharmaceuticals, Inc, Salt Lake City, UT.
authors: Shuping
authors: S
authors: Lai
authors: Astex Pharmaceuticals, Inc, Salt Lake City, UT.
authors: Michael V
authors: MV
authors: McCullar
authors: Astex Pharmaceuticals, Inc, Salt Lake City, UT.
authors: Koc-Kan
authors: KK
authors: Ho
authors: Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT.
authors: Daniel J
authors: DJ
authors: Albertson
authors: Tolero Pharmaceuticals, Inc, Lehi, UT.
authors: Lee T
authors: LT
authors: Call
authors: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT.
authors: Jared J
authors: JJ
authors: Bearss
authors: ARUP Laboratories, Salt Lake City, UT.
authors: Sheryl
authors: S
authors: Tripp
authors: Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT.
authors: Ting
authors: T
authors: Liu
authors: Tolero Pharmaceuticals, Inc, Lehi, UT.
authors: Bret J
authors: BJ
authors: Stephens
authors: Tolero Pharmaceuticals, Inc, Lehi, UT.
authors: Alexis
authors: A
authors: Mollard
authors: Tolero Pharmaceuticals, Inc, Lehi, UT.
authors: Steven L
authors: SL
authors: Warner
authors: Tolero Pharmaceuticals, Inc, Lehi, UT. Electronic address: dbearss@toleropharma.com.
authors: David J
authors: DJ
authors: Bearss
authors: Astex Pharmaceuticals, Inc, Salt Lake City, UT.
authors: Steven B
authors: SB
authors: Kanner
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002295:Carcinoma, Transitional Cell / Q000201:enzymology*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D060885:Multiplex Polymerase Chain Reaction; D009842:Oligopeptides / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D000090063:Proto-Oncogene Mas; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors*; D011724:Pyridazines / Q000494:pharmacology; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014161:Transduction, Genetic; D001749:Urinary Bladder Neoplasms / Q000201:enzymology*; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; C000715470:MAS1 protein, human; D009842:Oligopeptides; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D011724:Pyridazines; D034741:RNA, Small Interfering; C545188:SGI 1776; C117473:TP 3654; D014660:Vasoactive Intestinal Peptide; D051573:Proto-Oncogene Proteins c-pim-1; C406031:proto-oncogene proteins pim