Tyrphostins and other tyrosine kinase inhibitors.
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.
Levitzki
Alexander
A
The Silberman Institute for Life Sciences, Department of Biological Chemistry, The Hebrew University, Givat Ram Campus, Jerusalem 91904, Israel. levitzki@vms.huji.ac.il
Mishani
Eyal
E
D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D001549:Benzamides; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000069347:Erlotinib Hydrochloride; D016044:Fusion Proteins, bcr-abl; D000077156:Gefitinib; D006083:Graft Occlusion, Vascular / Q000517:prevention & control; D006801:Humans; D000068877:Imatinib Mesylate; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D011799:Quinazolines / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000502:physiology*; D020032:Tyrphostins / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; D020032:Tyrphostins; D000068877:Imatinib Mesylate; D000255:Adenosine Triphosphate; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor; D016044:Fusion Proteins, bcr-abl; D053614:Janus Kinase 2; D053616:Janus Kinase 3; D000077156:Gefitinib