Development of pseudosubstrate-based peptide and peptidomimetic inhibitors of p60ᶜ⁻ˢʳᶜ protein tyrosine kinase using combinatorial chemistry technology

Persistent Link:
http://hdl.handle.net/10150/289173
Title:
Development of pseudosubstrate-based peptide and peptidomimetic inhibitors of p60ᶜ⁻ˢʳᶜ protein tyrosine kinase using combinatorial chemistry technology
Author:
Kamath, Jayesh Ramrao
Issue Date:
2000
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Several protein tyrosine kinases and the signaling pathways in which they participate have emerged as attractive targets for drug design. Specific and potent PTK inhibitors not only represent a new class of anticancer agents but may also be used as a powerful research tool to study the role of PTK-dependent cellular pathways in normal or tumor cell growth and to dissect the redundancy in signal transduction pathways. Dr. Lam's laboratory has previously reported identification of efficient and specific peptide substrates for p60ᶜ⁻ˢʳᶜ PTK using one-bead one-peptide combinatorial library method (Lam et al., 1995; Lou et al., 1996a and b). Based on the structure of these peptide substrates, I have identified and characterized potent and selective peptide inhibitors of p60ᶜ⁻ˢʳᶜ PTK. Some of the identified peptide inhibitors were used as a research tool in this dissertation to investigate the active site of the enzyme p60ᶜ⁻ˢʳᶜ PTK. In addition to potency and selectivity, a major criterion for a successful src inhibitor is its cell permeability as src is located inside the cell. Peptides are generally impermeable to cell membrane. A major accomplishment of this dissertation is development of cell permeable peptidomimetic inhibitors of p60ᶜ⁻ˢʳᶜ PTK based on the identified dipeptide motif --Ile-Tyr- (-I-Y-). This dissertation describes identification of tetrameric and trimeric peptidomimetic inhibitors using a combination of two combinatorial methods, the 'one-bead one-compound' combinatorial method and the 'iterative' combinatorial method. Some of the identified inhibitors seem to selectively affect transformed cells versus normal cells at lower concentrations. A lot of still needs to be done to optimize these inhibitors. However, the accomplished work in this dissertation proves the feasibility of the pseudosubstrate peptide-based approach for the development of cell permeable peptidomimetic inhibitors as anti-cancer therapeutic agents.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Biology, Molecular.; Chemistry, Pharmaceutical.; Health Sciences, Immunology.; Health Sciences, Oncology.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Microbiology and Immunology
Degree Grantor:
University of Arizona
Advisor:
Lam, Kit S.; Marchalonis, John J.

Full metadata record

DC FieldValue Language
dc.language.isoen_USen_US
dc.titleDevelopment of pseudosubstrate-based peptide and peptidomimetic inhibitors of p60ᶜ⁻ˢʳᶜ protein tyrosine kinase using combinatorial chemistry technologyen_US
dc.creatorKamath, Jayesh Ramraoen_US
dc.contributor.authorKamath, Jayesh Ramraoen_US
dc.date.issued2000en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractSeveral protein tyrosine kinases and the signaling pathways in which they participate have emerged as attractive targets for drug design. Specific and potent PTK inhibitors not only represent a new class of anticancer agents but may also be used as a powerful research tool to study the role of PTK-dependent cellular pathways in normal or tumor cell growth and to dissect the redundancy in signal transduction pathways. Dr. Lam's laboratory has previously reported identification of efficient and specific peptide substrates for p60ᶜ⁻ˢʳᶜ PTK using one-bead one-peptide combinatorial library method (Lam et al., 1995; Lou et al., 1996a and b). Based on the structure of these peptide substrates, I have identified and characterized potent and selective peptide inhibitors of p60ᶜ⁻ˢʳᶜ PTK. Some of the identified peptide inhibitors were used as a research tool in this dissertation to investigate the active site of the enzyme p60ᶜ⁻ˢʳᶜ PTK. In addition to potency and selectivity, a major criterion for a successful src inhibitor is its cell permeability as src is located inside the cell. Peptides are generally impermeable to cell membrane. A major accomplishment of this dissertation is development of cell permeable peptidomimetic inhibitors of p60ᶜ⁻ˢʳᶜ PTK based on the identified dipeptide motif --Ile-Tyr- (-I-Y-). This dissertation describes identification of tetrameric and trimeric peptidomimetic inhibitors using a combination of two combinatorial methods, the 'one-bead one-compound' combinatorial method and the 'iterative' combinatorial method. Some of the identified inhibitors seem to selectively affect transformed cells versus normal cells at lower concentrations. A lot of still needs to be done to optimize these inhibitors. However, the accomplished work in this dissertation proves the feasibility of the pseudosubstrate peptide-based approach for the development of cell permeable peptidomimetic inhibitors as anti-cancer therapeutic agents.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectBiology, Molecular.en_US
dc.subjectChemistry, Pharmaceutical.en_US
dc.subjectHealth Sciences, Immunology.en_US
dc.subjectHealth Sciences, Oncology.en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplineMicrobiology and Immunologyen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorLam, Kit S.en_US
dc.contributor.advisorMarchalonis, John J.en_US
dc.identifier.proquest9983885en_US
dc.identifier.bibrecord.b40825206en_US
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