Recent advances in the design and discovery of small-molecule therapeutics targeting HER2/neu

The human epidermal growth factor receptor (HER) family is a highly explored and promising anticancer drug target. At present, several investigational agents targeted to the HER family of receptors are in various stages of development. Five drugs are already in the clinic for the treatment of cancers that overexpress HER family receptors. Two FDA-approved small-molecule drugs, gefitinib and erlotinib, inhibit HER1 tyrosine kinase activity. Two mAbs, cetuximab and panitumumab, target the extracellular domain of HER1, and another, trastuzumab, targets the extracellular domain of HER2. HER2 is a prominent member of the HER family of receptor tyrosine kinases and serves as a preferred dimerization partner for other HER family members. This paper reviews recently patented small-molecule inhibitors of HER2 receptor kinase activity, and inhibitors of HER2 expression and shedding. Apart from the well-explored quinazoline class of compounds (e.g., lapatinib), arylazole, benzodithiazole, pyrrolopyridazine, pyrrolotriazine and pyrrolopyrimidine classes of compounds were also claimed as HER2 tyrosine kinase inhibitors. Most of these compounds show considerable activity against all the HER family as well as members from different families of tyrosine kinases. It remains to be established how the combination of selective HER inhibitors compare with the single-agent pan-kinase inhibitors in disrupting HER family mediated signalling pathways. Such information is of paramount importance in the clinical development of HER-targeted inhibitors.