Ribosomal S6 kinase (RSK) modulators: a patent review

ABSTRACT

Introduction: The p90 ribosomal S6 kinases (RSK) are a family of Ser/Thr protein kinases that are downstream effectors of MEK1/2-ERK1/2. Increased RSK activation is implicated in the etiology of multiple pathologies, including numerous types of cancers, cardiovascular disease, liver and lung fibrosis, and infections.

Areas covered: The review summarizes the patent and scientific literature on small molecule modulators of RSK and their potential use as therapeutics. The patents were identified using World Intellectual Property Organization and United States Patent and Trademark Office databases. The compounds described are predominantly RSK inhibitors, but a RSK activator is also described. The majority of the inhibitors are not RSK-specific.

Expert opinion: Based on the overwhelming evidence that RSK is involved in a number of diseases that have high mortalities it seems surprising that there are no RSK modulators that have pharmacokinetic properties suitable for in vivo use. MEK1/2 inhibitors are in the clinic, but the efficacy of these compounds appears to be limited by their side effects. We hypothesize that targeting the downstream effectors of MEK1/2, like RSK, are an untapped source of drug targets and that they will generate less side effects than MEK1/2 inhibitors because they regulate fewer effectors.

KEYWORDS:

• p90RSK
• RSK
• SL0101
• FMK
• BIX 02565

Article highlights

• RSK is an unusual family of Ser/Thr kinases, which contain two non-identical kinase domains, the N-terminal kinase domain (NTKD) and the C-terminal kinase domain (CTKD). The NTKD phosphorylates a plethora of target substrates and the only known function of the CTKD is autoactivation.

• The preponderance of evidence supports the hypothesis that activated RSK is an important driver in the etiology of a number of diverse diseases with high mortalities.

• The majority of patents describe modulators of RSK kinase activity, which are either non-specific or poorly characterized.

• Despite the importance of RSK as a drug target there are no RSK-specific modulators with suitable pharmacokinetic properties for in vivo use.

• Targeting RSK as opposed to its upstream activator, MEK1/2, should provide therapies with less side effects as RSK controls fewer downstream effectors.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was funded by Susan G. Komen for the Cure (IIR12223770).