Discovery of the first isoform-specific sGC activator

The identification and characterization of a compound that selectively activates a particular isoform provides unique insight into the molecular differences and functional divergence between the isoforms. This not only allows for a more precise understanding of cellular signalling pathways but also potentially opens up new avenues for targeted therapy of diseases where dysregulated activity of a specific isoform is implicated. In humans, there are two distinct active isoforms of the soluble guanylyl cyclase (sGC): α1/β1 (GC-1) and α2/β1 (GC-2). In the present study we show that runcaciguat is the first isoform-specific sGC activator with a strong preference for GC-1. The activator exhibits antagonistic behaviour towards GC-2, leading to reduced efficacy of the nitric oxide donor DEA/NO. Similar results were generated with the related activator BAY-543. In addition, comparing the sGC activators BAY 60-2770 and BI 703704, a much stronger activation of GC-2 is measurable with BI 703704, whereas the potency of both activators in GC-1 is approximately the same. The classification of the investigated activators into mono- and dicarboxylic acids does not seem to be significant for the observed isoform specificity. It is tempting to hypothesize that the activation of GC-2 may rather increase with the lengthening of the lipophilic tail of the activators. Our laboratory is currently investigating this hypothesis.