Toward the development of new medicinal leads with selectivity for protein kinase C isozymes.

Tumor promoters such as phorbol esters bind strongly to protein kinase C (PKC) isozymes to induce their activation. Since each PKC isozyme is involved in diverse biological events in addition to tumor promotion, the isozymes serve as promising therapeutic targets. Tumor promoters bind to the C1A and/or C1B domain of conventional (alpha, betaI, betaII, and gamma) and novel PKC isozymes (delta, epsilon, eta, and theta). As these C1 domains play differential roles in PKC activation and their translocation in cells, the development of agents with binding selectivity for individual C1 domains is a pressing need. For this purpose, we established a synthetic C1 peptide library of all PKC isozymes. The library enabled us to identify indolactam-V (1) as a promising lead compound. Our diverse structure-activity studies on 1 indicated that the position of the hydrophobic substituent on the indole ring dominates the PKC isozyme- and C1 domain-selective binding rather than conformation of the nine-membered lactam. Moreover, we suggested that the indole ring of 1 could be involved in the CH/pi interaction with Pro-11 of the C1B domain of PKCdelta. This invaluable information will lead to the structural optimization of the PKCdelta ligand as exemplified by the design and synthesis of naphtholactam-V8 (21).