Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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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PMID:Tyrosine kinase blockers: new hope for successful cancer therapy. 1914 83

The majority of kinase inhibitors developed to date are competitive inhibitors that target the ATP binding site; however, recent crystal structures of Gleevec (imatinib mesylate, STI571, PDB: 1IEP), Nexavar (Sorafenib tosylate, BAY 43-9006, PDB: 1UWJ), and BIRB-796 (PDB: 1KV2) have revealed a secondary binding site adjacent to the ATP binding site known as the DFG-out allosteric binding site. The recent successes of Gleevec and Nexavar for the treatment of chronic myeloid leukemia and renal cell carcinoma has generated great interest in the development of other kinase inhibitors that target this secondary binding site. Here, we present a structural comparison of the important and similar interactions necessary for Gleevec(R), Nexavar, and BIRB-796 to bind to their respective DFG-out allosteric binding pockets and the selectivity of each with respect to c-Abl, B-Raf, and p38alpha. A structural analysis of their selectivity profiles has been generated from the synthesis and evaluation of 8 additional DFG-out allosteric inhibitors that were developed directly from fragments of these successful scaffolds.
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PMID:The design, synthesis, and evaluation of 8 hybrid DFG-out allosteric kinase inhibitors: a structural analysis of the binding interactions of Gleevec, Nexavar, and BIRB-796. 2062 96

Cancer growth and metastasis are often driven by activating mutations in, or gene amplications of, specific tyrosine or serine/threonine kinases. Kinase inhibitors (KIs) promised to provide targeted therapy-specifically inhibiting the causal or contributory kinases driving tumor progression while leaving function of other kinases intact. These inhibitors are of 2 general classes: (1) monoclonal antibodies that are typically directed against receptor tyrosine kinases or their ligands and (2) small molecules targeting specific kinases. The latter will be the focus of this review. This class of therapeutics has had some remarkable successes, including revolutionizing the treatment of some malignancies (eg, imatinib [Gleevec] in the management of chronic myeloid leukemia) and adding significantly to the management of other difficult to treat cancers (eg, sunitinib [Sutent] and sorafenib [Nexavar] in the management of renal cell carcinoma). But in some instances, cardiotoxicity, often manifest as left ventricular dysfunction and/or heart failure, has ensued after the use of KIs in patients. Herein we will explore the mechanisms underlying the cardiotoxicity of small-molecule KIs, hoping to explain how and why this happens, and will further examine strategies to deal with the problem.
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PMID:Why do kinase inhibitors cause cardiotoxicity and what can be done about it? 2072 98