This proposal outlines a strategy to design, synthesize, and examine the biological activity of new types of inhibitors for two families of hydrolytic enzymes; serine and cysteine proteases, and protein tyrosine phosphatases. The serine protease plasmin plays a role in both angiogenesis and metastasis in cancer development, while PTP1B and the Yersinia PTPase are important targets for the treatment of type II diabetes and bubonic plague, respectively. In the area of protease inhibitors, previous work has provided the rationale and mechanistic studies as the foundation for designing 4-heterocyclohexanone-based inhibitors. In the current proposal plans are outlined to increase the potency and specificity of the plasmin inhibitors through rational modifications, and then evaluate their activity in two biological assays that measure their ability to inhibit angiogenesis and invasion of the extracellular matrix. In addition, libraries of cyclohexanone-based protease inhibitors will be screened against a number of new cysteine proteases (cathepsins M, P, Q, and R) that play an important role in embryonic development in rodents. The new proteases were discovered recently by a collaborator on the project, R. W. Mason from the Dupont Hospital for Children. In the area of PTPase inhibitors, the studies that are propose build upon the initial discovery that aryl (?-ketocarboxylic acids can serve as the framework from which to construct potent PTPase inhibitors. There are two main objectives in this area. First, studies are proposed to improve the activity of an already potent divalent inhibitor (29, Ki = 700 nM) by using a high throughput method to synthesize several hundred analogs. These analogs are designed to increase the number and strength of the noncovalent interactions between the enzyme and inhibitor. A library of divalent inhibitors will also be synthesized and screened in order to optimize the structure of the linker region between two ?-ketoacid groups. Finally, the optimized inhibitors will be examined for their ability to inhibit dephosphorylation of the insulin receptor that is catalyzed by PTP1B.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Bio-Organic and Natural Products Chemistry Study Section (BNP)
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Fabian, Miles
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Brown University
Schools of Arts and Sciences
United States
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Xue, Fengtian; Seto, Christopher T (2010) Fluorogenic peptide substrates for serine and threonine phosphatases. Org Lett 12:1936-9
Xue, Fengtian; Seto, Christopher T (2009) Macrocyclic inhibitors for the serine protease plasmin. J Enzyme Inhib Med Chem 24:779-94
Hassanein, Mohamed; Xue, Fengtian; Seto, Christopher T et al. (2007) Development of a specific inhibitor for the placental protease, cathepsin P. Arch Biochem Biophys 464:288-94
Xie, Jian; Seto, Christopher T (2007) A two stage click-based library of protein tyrosine phosphatase inhibitors. Bioorg Med Chem 15:458-73
Xue, Fengtian; Seto, Christopher T (2006) Structure-activity studies of cyclic ketone inhibitors of the serine protease plasmin: design, synthesis, and biological activity. Bioorg Med Chem 14:8467-87
Xue, Fengtian; Seto, Christopher T (2005) Selective inhibitors of the serine protease plasmin: probing the S3 and S3' subsites using a combinatorial library. J Med Chem 48:6908-17
Xie, Jian; Seto, Christopher T (2005) Investigations of linker structure on the potency of a series of bidentate protein tyrosine phosphatase inhibitors. Bioorg Med Chem 13:2981-91
Xue, Fengtian; Seto, Christopher T (2005) A comparison of cyclohexanone and tetrahydro-4H-thiopyran-4-one 1,1-dioxide as pharmacophores for the design of peptide-based inhibitors of the serine protease plasmin. J Org Chem 70:8309-21
Chen, Yen Ting; Seto, Christopher T (2004) Parallel synthesis of a library of bidentate protein tyrosine phosphatase inhibitors based on the alpha-ketoacid motif. Bioorg Med Chem 12:3289-98
Abato, P; Conroy, J L; Seto, C T (1999) Combinatorial library of serine and cysteine protease inhibitors that interact with both the S and S' binding sites. J Med Chem 42:4001-9

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