Abstract
The development of tyrosine phosphorylation inhibitors has transformed the approach to cancer therapy and is likely to affect other fields of medicine. In spite of the conservation among protein tyrosine kinases (PTKs), one can develop small molecules that block the activity of a narrow spectrum of PTKs and that exhibit much less toxicity than the currently used chemotherapeutic agents. In this review, we discuss principles for inhibiting specific PTKs. We discuss (a) the birth of the concept of generating targeted, nontoxic signal transduction inhibitors, (b) the potential of substrate-competitive versus the more common ATP-competitive PTK inhibitors, (c) the combination of PTK inhibitors with other signal transduction inhibitors to induce apoptosis-the best way to induce the demise of the cancer cell, and (d) the potential to utilize PTK inhibitors/tyrphostins to attenuate nonmalignant pathological conditions, such as immune disorders, tissue rejection, and restenosis.
Publication types
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Research Support, Non-U.S. Gov't
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Review
MeSH terms
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Adenosine Triphosphate / chemistry
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Adenosine Triphosphate / metabolism
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / metabolism
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Antineoplastic Agents / therapeutic use
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Benzamides
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ErbB Receptors / antagonists & inhibitors
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Erlotinib Hydrochloride
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Fusion Proteins, bcr-abl
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Gefitinib
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Graft Occlusion, Vascular / prevention & control
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Humans
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Imatinib Mesylate
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Janus Kinase 2 / antagonists & inhibitors
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Janus Kinase 2 / metabolism
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Janus Kinase 3 / antagonists & inhibitors
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Janus Kinase 3 / metabolism
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
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Molecular Structure
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Piperazines / chemistry
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Piperazines / metabolism
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Piperazines / therapeutic use
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / metabolism
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Protein Kinase Inhibitors / therapeutic use
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Protein-Tyrosine Kinases* / antagonists & inhibitors
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Protein-Tyrosine Kinases* / metabolism
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Pyrimidines / chemistry
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Pyrimidines / metabolism
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Pyrimidines / therapeutic use
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Quinazolines / chemistry
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Quinazolines / metabolism
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Quinazolines / therapeutic use
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Receptors, Platelet-Derived Growth Factor / antagonists & inhibitors
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Receptors, Platelet-Derived Growth Factor / metabolism
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Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors
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Signal Transduction / physiology*
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Tyrphostins* / chemistry
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Tyrphostins* / metabolism
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Tyrphostins* / therapeutic use
Substances
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Antineoplastic Agents
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Benzamides
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Piperazines
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Protein Kinase Inhibitors
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Pyrimidines
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Quinazolines
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Tyrphostins
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Imatinib Mesylate
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Adenosine Triphosphate
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Erlotinib Hydrochloride
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ErbB Receptors
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Protein-Tyrosine Kinases
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Receptors, Platelet-Derived Growth Factor
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Receptors, Vascular Endothelial Growth Factor
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Fusion Proteins, bcr-abl
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Janus Kinase 2
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Janus Kinase 3
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Gefitinib