Emerging roles of targeted small molecule protein-tyrosine kinase inhibitors in cancer therapy.

摘要: Targeted protein-tyrosine kinase inhibitors (PTKIs) comprise a new, rapidly evolving class of low molecular weight anticancer drugs. Two members this class, imatinib (Gleevec) and gefitinib (Iressa), are currently approved for market use in the United States. This review discusses scientific history behind these two PTKI drugs, including role targeted cancer etiology, biochemistry selective inhibition, evaluation clinical efficacy, mechanisms whereby drug resistance has emerged. Other PTKIs undergoing also described, epidermal growth factor receptor (erlotinib, PKI166, CI-1033) designed to disrupt tumor vascularization (SU5416, SU6668, SU11248, PTK787, ZD6474). How might one apply current knowledge efficient development new agents that would target as-yet-unexploited oncogenic PTKs such as chimeric anaplastic leukemia kinases or Janus kinases? Ideally, targets should contain structurally distinct interaction epitopes, although it is not necessary epitopes be unique single target, because effective drugs may inhibit multiple involved an process. Oral availability highly desirable feature daily oral administration can maintain sustained efficacious plasma concentration, whereas intermittent parenteral not. Perhaps most importantly, must verify presence appropriate on case-by-case basis before selecting patient therapy. Thus, molecularly diagnostic tools will crucial ultimate success