Therapeutic targeting of p90 ribosomal S6 kinase

Abstract

The Serine/Threonine protein kinase family, p90 ribosomal S6 kinases (RSK) are downstream effectors of extracellular signal regulated kinase 1/2 (ERK1/2) and are activated in response to tyrosine kinase receptor or G-protein coupled receptor signaling. RSK contains two distinct kinase domains, an N-terminal kinase (NTKD) and a C-terminal kinase (CTKD). The sole function of the CTKD is to aid in the activation of the NTKD, which is responsible for substrate phosphorylation. RSK regulates various homeostatic processes including those involved in transcription, translation and ribosome biogenesis, proliferation and survival, cytoskeleton, nutrient sensing, excitation and inflammation. RSK also acts as a major negative regulator of ERK1/2 signaling. RSK is associated with numerous cancers and has been primarily studied in the context of transformation and metastasis. The development of specific RSK inhibitors as cancer therapeutics has lagged behind that of other members of the mitogen-activated protein kinase signaling pathway. Importantly, a pan-RSK inhibitor, PMD-026, is currently in phase I/1b clinical trials for metastatic breast cancer. However, there are four members of the RSK family, which have overlapping and distinct functions that can vary in a tissue specific manner. Thus, a problem for transitioning a RSK inhibitor to the clinic may be the necessity to develop isoform specific inhibitors, which will be challenging as the NTKDs are very similar to each other. CTKD inhibitors have limited use as therapeutics as they are not able to inhibit the activity of the NTKD but could be used in the development of proteolysis-targeting chimeras.

Mitochondrial Signatures Shape Phenotype Switching and Apoptosis in Response to PLK1 and RSK Inhibitors in Melanoma

“…To first examine the association between RSK expression and inflammation in human melanoma, we performed correlation analyses using the Skin Cutaneous Melanoma (SKCM) RNA-Seq data set of human melanoma tumors from TCGA PanCancer Atlas. We also included the analysis of transcripts encoding for putative off-targets of BI-D1870, a notorious non-selective RSK inhibitor (reviewed in 18 ). These analyses revealed that all RSK family members correlate positively with inflammation-associated transcripts ( Figure 1A ), while several BI-D1870 targets, such as PLK1, CDK2, and PTK2, showed a 4 negative correlation.…”

“…Despite the importance of these findings and the identification of new drug candidates, it is crucial to consider the selectivity of RSK inhibitors since some off-target effects may contribute to the observed anti-tumoral activity. One notorious unselective RSK inhibitor is BI-1870, which was shown to bind the active site of dozens of unrelated kinases such as Polo-like kinase (PLK) 1/3, aurora kinase B, PIK3, and exert RSK-independent effects ( 13–16 and reviewed in 17,18 ). For other promising compounds with good biodistribution, tolerability and specific anti-tumoral activities, data on selectivity is often incomplete or unpublished, which may be detrimental to the identification of molecular targets and understanding the mechanism of drug action.…”