Protein tyrosine phosphatases (PTPs) are important modulators of signal transduction pathways that regulate a wide range of physiological processes such as cell proliferation and differentiation, progression through the cell cycle, cell-cell communication, cell migration, metabolism, gene transcription, ion channel activity, the immune response and apoptosis/survival decisions. Deregulation of PTP activity results in aberrant tyrosine phosphorylation, which has been linked to the etiology of several human diseases, including cancer. The PRL (phosphatase of regenerating liver) phosphatases represent a novel class of PTPs that are important for controlling cellular growth and invasion. In particular, substantial evidence has accumulated that suggests an oncogenic role for PRL3 in the development of a number of tumorigenesis and metastasis processes. Ectopic expression of PRL3 enhances cell growth, causes cell transformation, and promotes tumor metastasis. Importantly, the phosphatase activity of PRL3 is required for the observed oncogenic activity. Consequently, PRL3 is a highly attractive target for cancer therapy. The goals of this application are to develop potent and selective small molecule PRL3 inhibitors and to evaluate their potential to be used as anti-cancer therapeutics. A multidisciplinary research program involving synthetic chemistry, high throughput screening, enzyme kinetics, cell biology, mutagenesis, and structural biology will be employed to: 1) Design and construct novel combinatorial libraries targeted to PRL3, 2) Identify and characterize potent and selective PRL3 inhibitors from the libraries, 3) Assess the cellular efficacy of the selected PRL3 inhibitors, and 4) Determine the molecular basis of PRL3 inhibition. Successful completion of this project will create a solid foundation upon which novel anti-cancer agents targeted to PRL3 can be developed. In addition, potent and selective PRL3 inhibitors acquired from this project will also serve as research tools to delineate the function of PRL3 in normal physiology and in the pathogenesis of certain cancers. Obtaining this knowledge is vital for understanding the PRL3-mediated tumor growth and metastasis, and for the development of novel anti-cancer therapies targeted to PRL3.

Public Health Relevance

The phosphatase PRL3 has been implicated in tumor growth and metastasis and thus represents an attractive target for anti-cancer therapy. The goals of this application are to develop potent and selective small molecule PRL3 inhibitors and to evaluate their potential to be used as anti-cancer agents.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA126937-05
Application #
8197256
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Jhappan, Chamelli
Project Start
2007-12-03
Project End
2012-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
5
Fiscal Year
2012
Total Cost
$303,925
Indirect Cost
$102,650
Name
Indiana University-Purdue University at Indianapolis
Department
Biochemistry
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
He, Rong-Jun; Yu, Zhi-Hong; Zhang, Ruo-Yu et al. (2014) Protein tyrosine phosphatases as potential therapeutic targets. Acta Pharmacol Sin 35:1227-46
He, Rongjun; Zeng, Li-Fan; He, Yantao et al. (2013) Small molecule tools for functional interrogation of protein tyrosine phosphatases. FEBS J 280:731-50
He, Yantao; Xu, Jie; Yu, Zhi-Hong et al. (2013) Discovery and evaluation of novel inhibitors of mycobacterium protein tyrosine phosphatase B from the 6-Hydroxy-benzofuran-5-carboxylic acid scaffold. J Med Chem 56:832-42
Loh, K; Merry, T L; Galic, S et al. (2012) T cell protein tyrosine phosphatase (TCPTP) deficiency in muscle does not alter insulin signalling and glucose homeostasis in mice. Diabetologia 55:468-78
He, Yantao; Zeng, Li-Fan; Yu, Zhi-Hong et al. (2012) Bicyclic benzofuran and indole-based salicylic acids as protein tyrosine phosphatase inhibitors. Bioorg Med Chem 20:1940-6
Loh, Kim; Fukushima, Atsushi; Zhang, Xinmei et al. (2011) Elevated hypothalamic TCPTP in obesity contributes to cellular leptin resistance. Cell Metab 14:684-99
Yu, Zhi-Hong; Chen, Lan; Wu, Li et al. (2011) Small molecule inhibitors of SHP2 tyrosine phosphatase discovered by virtual screening. Bioorg Med Chem Lett 21:4238-42
Li, Hui; Zhao, Zhenwen; Antalis, Caryl et al. (2011) Combination therapy of an inhibitor of group VIA phospholipase A2 with paclitaxel is highly effective in blocking ovarian cancer development. Am J Pathol 179:452-61
Piovan, Leandro; Wu, Li; Zhang, Zhong-Yin et al. (2011) Hypervalent organochalcogenanes as inhibitors of protein tyrosine phosphatases. Org Biomol Chem 9:1347-51
Liu, Sijiu; Yu, Zhihong; Yu, Xiao et al. (2011) SHP2 is a target of the immunosuppressant tautomycetin. Chem Biol 18:101-10

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