Activators and Inhibitors of Protein Kinase C (PKC): Their Applications in Clinical Trials

Abstract

Protein kinase C (PKC), a family of phospholipid-dependent serine/threonine kinase, is classed into three subfamilies based on their structural and activation characteristics: conventional or classic PKC isozymes (cPKCs; α, βI, βII, and γ), novel or non-classic PKC isozymes (nPKCs; δ, ε, η, and θ), and atypical PKC isozymes (aPKCs; ζ, ι, and λ). PKC inhibitors and activators are used to understand PKC-mediated intracellular signaling pathways and for the diagnosis and treatment of various PKC-associated diseases, such as cancers, neurological diseases, cardiovascular diseases, and infections. Many clinical trials of PKC inhibitors in cancers showed no significant clinical benefits, meaning that there is a limitation to design a cancer therapeutic strategy targeting PKC alone. This review will focus on the activators and inhibitors of PKC and their applications in clinical trials.

Keywords: activator; cancer; clinical trial; inhibitor; protein kinase C; signaling pathway.

Figure 1

Structure of PKC isozymes. All PKCs consist of a regulatory domain, a catalytic (kinase) domain, and variable regions (V1–V5). The regulatory domain of all PKCs includes a C1 domain with a pseudosubstrate motif. Additionally, cPKCs, nPKC, and aPKCs have a C2 domain that binds to Ca²⁺, a C2-like domain that cannot bind to Ca²⁺, and a PB1 domain in the regulatory region, respectively. The C3 and the C4 domain of all PKCs bind to ATP and substrate, respectively. Reproduced with permission from Kang, J.H. et al., Biotechnol. Adv.; published by Elsevier, 2012.

Figure 2

Chemical structure of C1 domain-binding PKC inhibitors (DAG competitive PKC inhibitors).

Figure 3

I. Chemical structure of C3 domain-binding inhibitors (ATP competitive PKC inhibitors): (A) indolocarbazole compounds, (B) Maleimide-based inhibitors. Bisindolylmaleimide (Bis) compounds (enzastaurin and ruboxistaurin) and sotrastaurin, and (C) other ATP competitive PKC inhibitor. II. Chemical structure of C4 domain-binding inhibitors (substrate competitive PKC inhibitors).

Figure 4

Chemical structure of atypical PKC inhibitors. These inhibitors show high potential inhibitory activity for PKCι/λ (PKCλ is the mouse homolog of PKCι) and PKCζ.

Figure 5

Chemical structure of PKC activators (C1 domain-binding ligands).