Preface Protein kinase C (PKC) has been a tantalizing target for drug discovery ever since it was first identified as the receptor for the tumor promoter phorbol ester in 19821. Although initial therapeutic efforts focused on cancer, additional diseases, including diabetic complications, heart failure, myocardial infarction, pain and bipolar disease were targeted as researchers developed a better understanding of the roles that PKC’s eight conventional and novel isozymes play in health and disease. Unfortunately, both academic and pharmaceutical efforts have yet to result in the approval of a single new drug that specifically targets PKC. Why does PKC remain an elusive drug target? This review will provide a short account of some of the efforts, challenges and opportunities in developing PKC modulators to address unmet clinical needs.

ML-IAP (melanoma inhibitor of apoptosis) is a potent anti-apoptotic protein that is strongly up-regulated in melanoma and confers protection against a variety of pro-apoptotic stimuli. The mechanism by which ML-IAP regulates apoptosis is unclear, although weak inhibition of caspases 3 and 9 has been reported. Here, the binding to and inhibition of caspase 9 by the single BIR (baculovirus IAP repeat) domain of ML-IAP has been investigated and found to be significantly less potent than the ubiquitously expressed XIAP (X-linked IAP). Engineering of the ML-IAP-BIR domain, based on comparisons with the third BIR domain of XIAP, resulted in a chimeric BIR domain that binds to and inhibits caspase 9 significantly better than either ML-IAP-BIR or XIAP-BIR3. Mutational analysis of the ML-IAP-BIR domain demonstrated that similar enhancements in caspase 9 affinity can be achieved with only three amino acid substitutions. However, none of these modifications affected binding of the ML-IAP-BIR domain to the IAP antagonist Smac (second mitochondrial activator of caspases). ML-IAP-BIR was found to bind mature Smac with low nanomolar affinity, similar to that of XIAP-BIR2-BIR3. Correspondingly, increased expression of ML-IAP results in formation of a ML-IAP-Smac complex and disruption of the endogenous interaction between XIAP and mature Smac. These results suggest that ML-IAP might regulate apoptosis by sequestering Smac and preventing it from antagonizing XIAP-mediated inhibition of caspases, rather than by direct inhibition of caspases.

Monolayer modification of alkylamine-protected γ-Fe 2 O 3 nanoparticles using functionalized alcohols and diols is presented. the stability of the modified nanoparticles was found to be dependent on the nature of the introduced alcohol: both bidentate surface-ligand bonding and steric blocking by bulky tail groups were necessary to produce systems resistant to agglomeration. EPR, UV-vis, and powder XRD analyses of the pre-and post-modified nanoparticles demonstrated that the core γ-Fe 2 O 3 functionality was unaffected by the change in monolayer composition. Finally, multiple ligands could be readily incorporated into the monolayer using a simultaneous displacement reaction.

A model system for the characterization of molecular recognition events in molecularly imprinted polymers (MIPs) is presented. The use of a biologically inspired, three-point hydrogen-bonding motif and a thin film polymeric matrix allows for pre- and post-polymerization binding properties to be characterized by infrared spectroscopy. A method to determine binding constants was developed and utilized before and after cross-linking. These values showed a 10-fold decrease in binding after polymerization, which was attributed to an increase in molecular confinement after polymerization and a change in the local structural environment of the binding cavity. Transport of the guest molecule was shown to be reversible.