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Tyrosine kinases as targets for cancer therapy
1Unit of Cellular Signaling, Department of Biological Chemistry, The Silverman Institute for Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel. levitzki@vms.huji.ac.il
Abstract:
Enhanced protein tyrosine kinase (PTK) activity correlates with the development of cancer and other proliferative diseases. The hypothesis that PTK inhibitors may be of value in the treatment of cancer led to the systematic synthesis of selective tyrosine phosphorylation inhibitors (tyrphostins) that show in vitro and in vivo anticancer activity. This review will provide an overview of research efforts in the development of tyrphostins such as AG 957, AG 1112, and AG 1318. Other tyrphostins discussed are AG 1478 and RG 13022, which are both epidermal growth factor receptor kinase inhibitors; AG 490, a Jak-2 kinase inhibitor; AG 1296, a PDGFR kinase inhibitor; and STI 571 (imatinib, Glivec/Gleevec; Novartis Pharma AG, Basel, Switzerland). STI 571 is now approved for the treatment of chronic myeloid leukemia and shows activity against gastrointestinal stromal tumors. The chemistry, kinetics, biological activity, and clinical potential of these compounds will be discussed.
Insights
Selective tyrosine phosphorylation inhibitors (tyrphostins) show promise for treating cancer by targeting enhanced protein tyrosine kinase (PTK) activity. Research highlights tyrphostins like STI 571, approved for leukemia, demonstrating anticancer potential.
Area of Science:
- Oncology
- Biochemistry
- Pharmacology
Background:
- Enhanced protein tyrosine kinase (PTK) activity is linked to cancer and proliferative diseases.
- PTK inhibitors, specifically tyrphostins, are investigated for their anticancer therapeutic potential.
Purpose of the Study:
- To review research on tyrphostin development, including their chemistry, kinetics, biological activity, and clinical potential.
- To provide an overview of specific tyrphostins with demonstrated in vitro and in vivo anticancer activity.
Main Methods:
- Systematic synthesis of selective tyrosine phosphorylation inhibitors (tyrphostins).
- Review of published research on various tyrphostins, including AG 957, AG 1112, AG 1318, AG 1478, RG 13022, AG 490, AG 1296, and STI 571.
- Discussion of specific kinase inhibition profiles (EGFR, Jak-2, PDGFR).
Main Results:
- Tyrphostins exhibit in vitro and in vivo anticancer activity.
- STI 571 (imatinib) is approved for chronic myeloid leukemia and shows efficacy in gastrointestinal stromal tumors.
- Specific tyrphostins target key kinases like EGFR, Jak-2, and PDGFR.
Conclusions:
- Tyrphostins represent a valuable class of compounds for cancer therapy.
- Further research into the chemistry, kinetics, and clinical application of tyrphostins is warranted.
- Targeted PTK inhibition offers a promising strategy for managing proliferative diseases.