A patent perspective of RSK inhibitors to treat cancer (2020-present).

introductionThe Ser/Thr protein kinase family, p90 ribosomal S6 kinase (RSK), can be activated by inputs from ERK1/2, PDK1 and in some cases MK1/MK2. Dysregulated RSK activity is implicated in diseases associated with inflammation such as cancer. There are four RSK family members of which RSK1/2 are tumor promoters whereas RSK3/4 can act as tumor suppressors. AREAS COVERED: The review summarizes patents that have identified compounds that decrease RSK activity. These patents all focus on the use of RSK inhibitors as cancer therapeutics. The patents were identified using the World Intellectual Property Organization, United States Patent and Trademark Office, and Derwent World Patents Index databases. EXPERT OPINION: The compounds disclosed in this patent review do not exhibit isoform specificity and there is limited or no information on selectivity and on target activity. The importance of RSK as a target is demonstrated by transition of the pan-RSK inhibitor, PMD-026, to phase 2 for metastatic breast cancer. RSK isoforms differ in their contributions to transformation. Therefore, specific inhibitors are needed, which is challenging as RSK kinase domains are similar. It is possible that PROTACs for RSK2 and RSK4 can be generated by exploiting their allosteric binding pockets with SL0101 or floxacin antibiotics, respectively.