Cancer metastasis therapeutic targets and drug discovery: emerging small-molecule protein kinase inhibitors

Abstract

Cancer metastasis is a significant problem and a tremendous challenge to drug discovery relative to identifying key therapeutic targets as well as developing breakthrough medicines. Recent progress in unravelling the complex molecular circuitry of cancer metastasis, including receptors, intracellular proteins and genes, is highlighted. Furthermore, recent advances in drug discovery to provide novel proof-of-concept ligands, in vivo effective lead compounds and promising clinical candidates, are summarised. Such drug discovery efforts illustrate the integration of functional genomics, cell biology, structural biology, drug design, molecular/cellular screening and chemical diversity (e.g., small molecules, peptides/peptidomimetics, natural products, antisense, vaccines and antibodies). Promising therapeutic targets for cancer metastasis have been identified, including Src, focal adhesion kinase, the integrin receptor, the vascular endothelial growth factor receptor, the epidermal growth factor receptor, Her-2/neu, c-Met, Ras/Rac GTPases, Raf kinase, farnesyl diphosphate synthase (i.e., amino-bisphosphonate therapeutic target) and matrix metalloproteases within the context of their implicated functional roles in cancer growth, invasion, angiogenesis and survival at secondary sites. Clinical and preclinical drug discovery is described and emerging small-molecule inhibitors of protein kinases are highlighted.

• angiogenesis
• apoptosis
• bisphosphonates
• bone metastasis
• CDK
• E-cadherin
• EGF-R
• focal adhesion kinase
• IGF-R
• integrin receptor
• integrin-linked kinase
• mammalian target of rapamycin
• MAPK
• metastasis suppressor genes
• MMP
• NF-kB
• PI3K
• protein kinase
• Ras farnesyl protein transferase
• signal transduction inhibition
• Src
• tumour suppressor genes
• VEGF-R