Irreversible inhibitors of the erbB family of protein tyrosine kinases

The erbB family of transmembrane receptor tyrosine kinases initiates a large number of cellular signalling pathways. Their over-expression in human tumours correlates with poor prognosis, and they have become important targets for drug development. The 4-anilinoquinazolines are potent and selective ATP site inhibitors of these enzymes, especially erbB1 (epidermal growth factor receptor). Structure-activity studies for binding at the ATP site are narrow, consistent with homology and crystal structure-binding models. Combinations of small lipophilic groups at the 3′-position of the aniline and electron-donating groups at the 6- or 7-positions of the quinazoline result in extremely potent (picomolar) reversible inhibitors, several of which are in clinical trial. Observation that the erbB family of enzymes contains a unique Cys residue (Cys773) close to the ATP-binding site prompted the development of irreversible inhibitors, the most successful being 6-acrylamides and related butynamides, which show significantly improved in vivo antitumour activity compared with closely related reversibly binding compounds. Solubilising side chains can be placed either at the terminus of the alkylating unit or at the quinazoline C-7, and examples of both types are in clinical trial. Both reversible and irreversible inhibitors synergise with a variety of DNA-damaging anticancer drugs, and it is likely that the greatest impact of these agents will be in combination therapy.