Recent Advances in the Design and Discovery of Small-molecule Therapeutics Targeting HER2/neu

The human epidermal growth factor receptor (HER) family is a highlyexplored and promising anticancer drug target. At present, several investigationalagents targeted to the HER family of receptors are in variousstages of development. Five drugs are already in the clinic for the treatmentof cancers that overexpress HER family receptors. Two FDA-approvedsmall-molecule drugs, gefitinib and erlotinib, inhibit HER1 tyrosine kinaseactivity. Two mAbs, cetuximab and panitumumab, target the extracellulardomain of HER1, and another, trastuzumab, targets the extracellulardomain of HER2. HER2 is a prominent member of the HER family of receptortyrosine kinases and serves as a preferred dimerization partner forother HER family members. This paper reviews recently patentedsmall-molecule inhibitors of HER2 receptor kinase activity, and inhibitors ofHER2 expression and shedding. Apart from the well-explored quinazolineclass of compounds (e.g., lapatinib), arylazole, benzodithiazole, pyrrolopyridazine,pyrrolotriazine and pyrrolopyrimidine classes of compounds werealso claimed as HER2 tyrosine kinase inhibitors. Most of these compoundsshow considerable activity against all the HER family as well as membersfrom different families of tyrosine kinases. It remains to be establishedhow the combination of selective HER inhibitors compare with the single-agent pan-kinase inhibitors in disrupting HER family mediated signallingpathways. Such information is of paramount importance in the clinicaldevelopment of HER-targeted inhibitors.