Inhibitors of Protein Kinase C and Related Receptors for the Lipophilic Second-Messenger sn-1,2-Diacylglycerol

Toxic natural products, selected by evolution both for activity against crucial biological targets and for potency, have made major contributions in highlighting such targets and in defining their functions. The phorbol esters, initially isolated on the basis of their activity as tumor promoters and as acute irritants, were found to have dramatic biological effects in virtually every system in which they were examined (1). We now appreciate that the phorbol esters function as ultrapotent analogs of the lipophilic second messenger sn-1,2-diacylglycerol (DAG) and that phorbol ester receptors identify high-affinity targets in DAG signaling (2), of which protein kinase C (PKC) has been most thoroughly studied (3–7).