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Conventional anticancer therapy using cytotoxic drugs lacks selectivity and is prone to toxicity and drug resistance. Anticancer therapies targeting aberrant growth factor receptor signaling are gaining interest. The erbB receptor family belongs to the type I, the receptor tyrosine kinases class, and comprises EGFR, HER-2, HER-3, and HER-4. It has been targeted for solid tumor therapy, including breast, ovarian, colon, head-and-neck, and non-small-cell lung cancers. This review summarizes structural aspects of this class of growth factor receptors, their oncogenic expression, and various pharmacological interventions including biological products and small molecules that inhibit these enzymes. We have also discussed various mutations that occur in EGFR and their consequences on anticancer therapy.

The structures of the 16-residue fusion domain (or fusion peptide, FP) of the human immunodeficiency virus gp41 fusion protein, two of its mutants, and a shortened peptide (5-16) were studied by molecular dynamics simulation in an explicit palmitoyloleoylphosphoethanolamine bilayer. The simulations showed that the active wild-type FP inserts into the bilayer approximately 44 degrees +/- 6 degrees with respect to the bilayer normal, whereas the inactive V2E and L9R mutants and the inactive 5 to 16 fragment lie on the bilayer surface. This is the first demonstration by explicit molecular dynamics of the oblique insertion of the fusion domain into lipid bilayers, and provides correlation between the mode of insertion and the fusogenic activity of these peptides. The membrane structure of the wild-type FP is remarkably similar to that of the influenza HA(2) FP as determined by nuclear magnetic resonance and electron spin resistance power saturation. The secondary structures of the wild-type FP and the two inactive mutants are quite similar, indicating that the secondary structure of this fusion domain plays little or no role in affecting the fusogenic activity of the fusion peptide. The insertion of the wild-type FP increases the thickness of the interfacial area of the bilayer by disrupting the hydrocarbon chains and extending the interfacial area toward the head group region, an effect that was not observed in the inactive FPs.

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In this early phase of the new era of molecularly targeted patient friendly cancer chemotherapy, there is a need for novel viable anticancer molecular targets. The MDM2 oncoprotein has been validated as a potential target for cancer drug development. MDM2 amplification and/or overexpression occur in a wide variety of human cancers, several of which can be treated experimentally with MDM2 antagonists. MDM2 interacts primarily with the p53 tumor suppressor protein in an autoregulatory negative feedback loop to attenuate p53's cell cycle arrest and apoptosis functions. Inhibition of the p53-MDM2 interaction has been shown to cause selective cancer cell death, as well as sensitize cancer cells to chemotherapy or radiation effects. Consequently, this interaction has been the main focus of anticancer drug discovery targeted to MDM2. The promotion of the proteasomal degradation of the p53 protein by MDM2 is central to its repression of the tumor suppressor functions of p53, and many proteins impinge upon this activity, either enhancing or inhibiting it. MDM2 also has oncogenic activity independent of its interaction with p53, but this has so far not been explored for drug discovery. Among the approaches for targeting MDM2 for cancer therapy, small molecule antagonists have recently featured as effective anticancer agents in experimental models, although the repertoire is currently limited and none has yet entered human clinical trials. Small molecules that have been reported to disrupt the p53-MDM2 binding, thereby enhancing p53 activity to elicit anticancer effects include the following: synthetic chalcones, norbornane derivatives, cis-imidazoline derivatives (Nutlins), a pyrazolidinedione sulfonamide and 1,4-benzodiazepine-2,5-diones, as well as tryptophan derivatives. In addition to compounds disrupting p53pMDM2 binding, three compounds have been discovered that are effective in inhibiting the E3 ligase activity of MDM2 towards p53, and should serve as leads for drug discovery targeting this aspect of the p53-MDM2 interaction as well. These compounds were discovered from library screening and/or structure-based rational drug design strategies.