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Molecular Targets in the Discovery and Development of Novel Antimetastatic Agents: Current Progress and Future Prospects.
Clin Exp Pharmacol Physiol. 2013 Mar 27;
Authors: Szinwong M, Sidek SM, Mahmud R, Stanslas J
Abstract
Tumour invasion and metastasis have been recognised as major causal factors in the morbidity and mortality among cancer patients. Many advances in the knowledge of cancer metastasis have yielded an impressive array of attractive drug targets, including enzymes, receptors, and multiple signalling pathways. This review summarizes the molecular pathogenesis of metastasis and the identification of novel molecular targets utilised in the discovery of antimetastatic agents. Several promising targets have been highlighted, which include receptor tyrosine kinases (RTKs), effector molecules involved in angiogenesis, matrix metalloproteinases (MMPs), urokinase plasminogen activator (uPA), adhesion molecules and their receptors, signalling pathways (eg, phosphatidylinositol 3-kinase (PI3K), phospholipase C?1 (PLC?1), MAP kinases (MAPK), c-Src kinase, c-Met kinases and heat shock protein (HSP 90)). The discovery and development of potential novel therapeutics for each of the targets are also discussed in this review. Among these, the most promising agents that showed remarkable clinical outcome are anti-angiogenic agents (eg, bevacizumab). Newer agents, such as c-Met kinase inhibitors, are still undergoing preclinical studies and have yet had their clinical efficacy to be proven. Some therapeutics, such as first-generation MMP inhibitors (MMPIs, eg, marimastat) and more selective versions of them (eg, prinomastat, tanomastat), have undergone clinical trials. Unfortunately, these drugs produced serious adverse effects and led to premature termination of their development. In the future, third-generation MMPIs and inhibitors of signalling pathways and adhesion molecules could form valuable novel classes of drugs in the anticancer armamentarium to combat metastasis. � 2013 The Authors Clinical and Experimental Pharmacology and Physiology � 2013 Wiley Publishing Asia Pty Ltd.
PMID: 23534409 [PubMed - as supplied by publisher]
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