**5. State of atypical PKC inhibitors**

We have discussed the effects of five aPKC specific inhibitors throughout this chapter. The structures of these compounds are shown in **Figure 5**.

Atypical PKCs were first considered as a novel therapeutic target by Stallings-Mann et al. in 2006. They screened aurothiomalate as a potent inhibitor of the interaction between PB1 domain of PKC-ι and Par6 [87]. Half maximal inhibitory concentration (IC50) of aurothiomalate ranged from 300 nM to 100 μM and indicated that some cell lines are insensitive (i.e. H460 and A549 lung cancer cells) to the inhibitor [87].

Blázquez et al. tested calphostin C and chelerythrine against West Nile virus (WNV) which significantly inhibit WNV multiplication in cell culture without affecting cell viability. They report that PKCs have also been implicated in different steps during viral replication. Calphostin C and chelerythrine two wide range PKC inhibitors that target all three PKC classes. Results indicate that atypical PKCs are involved in WNV multiplication process which can be effectively retard using said inhibitors [88].

Kim et al. reported the application of Echinochrome A as an inducer of cardiomyocyte differentiation from mouse embryonic stem cells. Echinochrome A was

#### **Figure 5.**

*Structures of the aPKC specific inhibitors (ACPD, DNDA, ζ-Stat, ICA-1S and ICA-1T). chemical structures of ACPD (a) and DNDA are specific to both PKC-ι and PKC-ζ, ζ-Stat (C) is specific to PKC-ζ while ICA-1S (D) and ICA-1T (E) are specific to PKC-ι. molecular weights (MW) of ACPD (140.14 g/mol), DNDA (318.32 g/mol), ζ-Stat (MW = 384.34 g/mol), ICA-1S (MW = 256.26 g/mol) and ICA-1T (MW = 336.24 g/ mol), respectively.*

**35**

**Author details**

and Mildred Acevedo-Duncan\*

provided the original work is properly cited.

Wishrawana S. Ratnayake, Christopher A. Apostolatos

\*Address all correspondence to: macevedo@usf.edu

*Atypical Protein Kinase Cs in Melanoma Progression DOI: http://dx.doi.org/10.5772/intechopen.83410*

binding of Echinochrome A with PKC-ι [89].

based on azaindole [90].

**Acknowledgements**

**Conflict of interests**

Foundation.

extracted from sea urchins. They investigated the potential use of Echinochrome A as an aPKC specific inhibitor and found that IC50 for PKC-ι is 107 μM under *in-vitro* kinase assay conditions. Molecular docking simulation results suggested a direct

An important study by Kwiatkowski et al. identified an azaindole-based scaffold for the development of more potent and specific PKC-ι inhibitors. They described fragmented based approach an introduced a new class of potential aPKC inhibitors

The authors acknowledge the generous financial contributions from the Frederick H. Leonhardt Foundation, David Tanner Foundation, Bradley Zankel Foundation, Inc., Kyrias Foundation, Brotman Foundation of California, Baker Hughes Foundation, Irving S. Cooper Family Foundation, and the Creag

The authors declare that they have no competing interests.

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Department of Chemistry, University of South Florida, Tampa, FL, USA

*Atypical Protein Kinase Cs in Melanoma Progression DOI: http://dx.doi.org/10.5772/intechopen.83410*

extracted from sea urchins. They investigated the potential use of Echinochrome A as an aPKC specific inhibitor and found that IC50 for PKC-ι is 107 μM under *in-vitro* kinase assay conditions. Molecular docking simulation results suggested a direct binding of Echinochrome A with PKC-ι [89].

An important study by Kwiatkowski et al. identified an azaindole-based scaffold for the development of more potent and specific PKC-ι inhibitors. They described fragmented based approach an introduced a new class of potential aPKC inhibitors based on azaindole [90].
