Molecular glue degraders (MGDs) represent a promising strategy for targeted protein degradation within cells. While chemoproteomics has unveiled hundreds of potential MGD targets, very few proteins are degraded by highly selective and potent MGDs. Here, we developed a novel glutarimide analog with a tetrahydroimidazo[1,2-a]pyrazine scaffold that exhibited strong NIMA-related kinase 7 (NEK7) degradation potential. Further optimization led to the identification of LC-04-045 as a leading NEK7 MGD candidate, demonstrating potent activity with a half-maximal degradation (DC50) of 7 nM and a maximum degradation (Dmax) of 90 % in MOLT-4 cells. Notably, LC-04-045 displayed high selectivity for NEK7 across the proteome. Mechanistic studies indicated that the degradation was mediated by the ubiquitin-proteasome system (UPS) and relied on the glycine 57 (G57)-containing degron motif in NEK7. Additionally, two amino acids adjacent to the degron motif were found to be crucial for modulating the compound's selectivity and potency, underscoring the significance of neighbouring residues in MGD design. Moreover, LC-04-045 effectively inhibited secretion of the downstream cytokines, including IL-1β and IL-18, highlighting the potential therapeutic applications of NEK7 MGDs in treating inflammatory diseases.
Keywords: Molecular Glue Degrader; NEK7 Kinase; NLRP3 Inflammasome; NLRP3 activation; Protein Degradation.
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