Sylvain, A.; Stoehr, N.; Ma, F.; Cernijenko, A.; Schroeder, M.; Khoshouei, M.; Vogelsanger, M.; Schoenboerner, M.; Burke, A.; Pasupuleti, R.; Solomon, J.; Paulk, J.; Xu, L.; Dawson, J.; Begue, D.; Lefeuvre, P.; Ahrne, E.; Hofmann, A.; Dickson, C. J.; Arabin, P.; Zimmerlin, A.; Kiffe, M.; Froehlicher, M.; Boersig, T.; Elhajouji, A.; Brichet, M.; Menon, S.; Liu, S.; Mueller, M.; Wartchow, C.; Lin, J.; Cardona Gloria, Y.; Dickhoefer, S.; Weber, A. N. R.; Welzel, T.; Kuemmerle-Deschner, J.; Farady, C. J.; Pulz, R.; Bornancin, F.; Buckley, D. L.; Bassi, Z. I.

The NLRP3 (NACHT-, leucine-rich repeat [LRR]- and pyrin domain [PYD]- containing protein 3) inflammasome is a cytoplasmic signaling complex that promotes inflammation in response to signals from infection and cellular damage. Increased activation of the NLRP3 inflammasome is linked to numerous diseases including gout, osteoarthritis, cardiovascular disease, neuroinflammatory diseases and cancer, which has prompted the search for therapeutics that can inhibit the NLRP3 pathway. Recent work suggested that NIMA-related kinase 7 (NEK7) may be required for proper assembly and activation of the NLRP3 inflammasome independent of its kinase activity, and that hence reduction of NEK7 protein levels may block NLRP3 activation. Since NEK7 contains a glycine beta hairpin loop structural degron found in many targets of cereblon (CRBN) molecular glue degraders, we used this strategy to degrade NEK7 and inhibit the NLRP3 inflammasome. We identified NK7-902, a CRBN glue degrader of NEK7. NK7-902 potently and selectively degraded NEK7 in human primary monocytes, peripheral blood mononuclear cells (PBMCs) and whole blood. Unexpectedly, full NEK7 degradation led to only partial blockade of NLRP3-dependent interleukin-1beta (IL-1beta) release in these cells under different stimulation conditions, with the extent of IL-1beta inhibition varying greatly across donors. Unlike most CRBN glue degraders, NK7-902 degraded NEK7 in mouse cells and efficiently inhibited NLRP3-dependent IL-1beta release in a mouse cryopyrin-associated syndrome (CAPS) model. By contrast, oral administration of NK7-902 in non-human primates led to profound and long lasting NEK7 degradation but only transiently blocked IL-1beta production in blood. Collectively, our data suggest that NEK7 is involved but may not be strictly required for NLRP3 activation in primates and humans.