Tyrosine kinase blockers: new hope for successful cancer therapy.
Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment.
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SU 11248 Sutent AMN107 Nilotinib INNO-406 NS-187 Lapatinib Lapatinib ditosylate Tykerb GW-572016 Tyrosine Canertinib CI-1033 Zactima ZD6474 Vatalanib PTK787 ZK 222584 Sorafenib Bay 43-9006 Nexavar Dasatinib Leflunomide SU101 Arava tyrosine tyrosine Imatinib Imatinib mesylate Gleevec STI571 STI571 BMS-354825 Tyrosine Tyrosine kinases ABL non-receptor cytoplasmic kinase VEGF receptor kinase c-KIT TK tyrosine kinase TKs Gefitinib TKs tyrosine kinase TKs kinase Bcr Abl Tyrosine kinase Iressa Erlotinib OSI-774 Tarceva Sunitinib