Design and synthesis of isoform selective c-Jun N-terminal kinase (JNK) inhibitors

The JNK subfamily of mitogen activated protein kinases (MAPKs) consists of three isoforms and a total of 10 splice variants with highly conserved ATP-binding pockets and great structural similarity towards other MAPKs. A multitude of in vivo mouse studies and siRNA approaches indicate different and sometimes even opposing roles of the individual isoforms in the development and progression of various diseases, such as neurodegenerative disease, inflammatory diseases and cancer. Accordingly, even though the high isoform similarity creates a major challenge, it has been of great interest to both academia and industry in recent years to develop isoform selective small molecule inhibitors for potential clinical use (e.g. CC-90001/ NCT05625412) as well as high quality chemical probes for research purposes.
Our research is based on a known class of JNK-inhibitors that showed insufficient selectivity towards the single isoforms. Employing a classical structure based medicinal chemistry approach we were able to further develop this scaffold via iterative optimisation. The resulting large set of designed inhibitors was screened towards JNK 1, 2 and 3 selectivity and the most selective compounds were further tested for their ADME properties. With remarkable isoform selectivity, high metabolic stability in mouse liver microsomes as well as promising pharmacokinetic properties, inhibitors were found which can serve as a toolbox for the further development of JNK inhibitors in vitro and in vivo.