Protein kinase Cα and ε small-molecule targeted therapeutics: A new roadmap to two Holy Grails in drug discovery?

Protein kinase (PK)Cα and ε are rational targets for cancer therapy. However, targeted experimental therapeutics that inhibit PKCα or ε are unavailable. The authors established recently that covalent modification of an active-site cysteine in human PKCε, Cys452, by small molecules, for example 2-mercaptoethanolamine, is necessary and sufficient to render PKCε kinase-dead. Cys452 is conserved in only eleven human protein kinase genes, including PKCα. Therefore, the design of small molecules that bind PKC active sites with an electrophile substituent positioned proximal to the Cys452 side chain may lead to targeted therapeutics that selectively inhibit PKCε, PKCα or other PKC isozymes.