3-phosphoinositide-dependent protein kinase 1 (PDK1) is the pivotal element of the phosphatidylinositol 3 kinase (PI3K) signaling pathway because it phosphorylates Akt/PKB through interactions with phosphatidylinositol 3,4,5 phosphate.

An Overview of PDK-1

3-phosphoinositide-dependent protein kinase-1 (PDK-1) is a serine/threonine protein kinase that is a member of the AGC kinase family. PDK-1 was first confirmed by Phil Cohen et al in 1997. PDK-1 is a polypeptide enzyme consisting of 556 amino acids (aa), which exists in monomeric form in vivo, with an N-terminal kinase domain (70-359aa) and a C-terminal PH domain (459-550aa). PDK-1 regulates signal transduction of various growth factors and proto-oncogenes, and is capable of phosphorylating and activating other protein kinases in at least 23 AGC kinase families. These kinases include , p70 ribosomal S6 kinase (S6K), and serum and glucocorti⁃coid-induced kinase (SGK). These kinases downstream of PDK-1 are closely related to the growth and proliferation of cells. PDK-1 is an important member of the PI3K/Akt signaling pathways. PDK-1 plays an important role in cell growth, proliferation and metabolism, and its abnormal activation is closely related with tumor formation.

Inhibition of PDK-1

PDK-1 kinase inhibitors include pyrimidine derivatives, quinolinone derivatives, and anthrone derivatives. Pyrimido-rings PDK-1 kinase inhibitors can be further classified into anthraquinones, pyrrolopyrimidines, and thienopyrimidinones. These compounds all have a core structure of N-hetero-membered 5-membered ring and N-hetero-membered ring. The natural cyclic peptide RA-V extracted from yarrow has shown anticancer activity. Fang et al. studied its anti-cancer mechanism and found that the cyclic peptide RA-V induces apoptosis by participating in the mitochondrial pathway dependent on the PI3K/Akt signaling pathway.

PDK-1 and diseases

The PI3K/Akt pathway is associated with a number of growth factors and proto-oncogenes and is closely related to the development of many human tumors. Akt is catalytically activated to promote tumor formation by inhibiting apoptosis, and stimulating cell proliferation and metabolism, and angiogenesis. While PDK-1 is an integral part of the PI3K/Akt pathway, signal transduction of PDK-1 is closely related to the development of cancer. Studies have shown that about 50% of cancers such as breast cancer, lung cancer, and prostate cancer cells over-express PDK-1. Therefore, PDK-1 inhibitors are expected to provide new ideas for cancer treatment.


Fang X.Y., Chen W., Fan J.T., et al. (2013) Plant cyclopeptide RA-V kills human breast cancer cells by inducing mitochondria-mediated apoptosis through blocking PDK-1 AKT interaction. Toxicol Appl Pharmacol, 267(1): 95-103.

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