Small‐Molecule Inhibitors of PDK1

Abstract

Signal transduction of many growth factors and oncogenes is mediated by 3-phosphoinositide-dependent protein kinase-1 (PDK1), a master regulator of a number of downstream signal protein kinase cascades. Hence, PDK1 represents a convergence point for receptor tyrosine kinase and cytokine-mediated pathways for the regulation of vital cell processes such as cell survival and proliferation. Pathological upregulation of PDK1 signalling due to constitutive growth factor receptor activation and/or PTEN (phosphatase and tensin homologue) mutations significantly triggers downstream signalling, e.g. PKB/Akt, which subsequently promote proliferative events such as tumour invasiveness, angiogenesis, and progression. Consistent with this, a mouse model expressing low levels of PDK1 is protected from tumourigenesis resulting from loss of PTEN. Because more than 50 % of all human cancers possess significant overstimulation of the PDK1 signalling pathway, inhibition of this protein kinase by small molecules is predicted to result in effective inhibition of cancer cell proliferation and thus be therapeutically beneficial. Various classes of small-molecule PDK1 inhibitors have been published in patents and papers. Herein we present for the first time a comprehensive collection of small molecules reported to interact with PDK1, and we refer to their biological characterisation in terms of activity and selectivity for PDK1.

Discovery of PDK1 Kinase Inhibitors with a Novel Mechanism of Action by Ultrahigh Throughput Screening

“…Given the central role of the phosphoinositide 3-kinase pathway in human diseases, including cancer and diabetes, compounds that modulate PDK1 activity may be useful as therapeutic agents. Indeed, the patent literature disclosed to date reflects a considerable pharmaceutical interest in targeting this enzyme (20). However, the overwhelming majority of the disclosed PDK1 inhibitors are relatively nonselective ATP analogs.…”

“…Known PDK1 inhibitors belonging to the tetracyclic and tricyclic classes (33,34,36) were identified, thus validating the screening assays. To focus on the novel scaffolds, the next round of attrition included 720 hits that were structurally similar to known inhibitors of PDK1 (20). The structural clustering of the remaining hits generated 1,528 centroids with ϳ1,000 singletons, resulting in a list of ϳ2,000 structurally novel diverse hits selected for further follow-up.…”

Repression of cancer cell senescence by PKCι

“…This leads to the activation of multiple downstream kinases through phosphoinositidedependent kinase-1 (PDK1). While PKB/Akt is the most widely studied of these kinases, multiple other kinases also require PDK1 phosphorylation for their activation, including the atypical PKCs (Peifer and Alessi, 2008).…”

Small molecule inhibition of phosphatidylinositol-3,4,5-triphosphate (PIP3) binding to pleckstrin homology domains

“…Although lipid-protein interactions mediate PI3K signaling and are frequently deregulated in cancer, most therapeutic strategies targeting the PI3K pathway have focused on inhibitors for downstream targets, including PDK1 (8) and Akt (9). Phospholipidprotein interactions have not been as actively targeted, even though lipid molecules are among the most important classes of second messengers.…”