一种基于cereblon的NEK7胶水降解剂以依赖于上下文的方式调节NLRP3炎性小体。
A cereblon-based glue degrader of NEK7 regulates NLRP3 inflammasome in a context-dependent manner.
作者信息
Sylvain Aude, Stoehr Natacha, Ma Fupeng, Cernijenko Artiom, Schröder Martin, Khoshouei Maryam, Vogelsanger Melanie, Schoenboerner Michel, Burke Ashley, Rao Pasupuleti, Solomon Jonathan M, Paulk Joshiawa, Xu Lei, Dawson Janet, Begue Damien, Lefeuvre Peggy, Ahrne Erik, Hofmann Andreas, Dickson Callum J, Arabin Philip, Zimmerlin Alfred, Kiffe Michael, Froehlicher Mirjam, Boersig Theresa, Elhajouji Azeddine, Brichet Murielle, Menon Suchithra, Liu Shanming, Mueller Matthias, Wartchow Charles A, Lin James, Gloria Yamel Cardona, Dickhöfer Sabine, Weber Alexander N R, Welzel Tatjana, Kuemmerle-Deschner Jasmin, Farady Christopher J, Pulz Robert, Bornancin Frederic, Buckley Dennis L, Bassi Zuni I
机构信息
Novartis Biomedical Research, Basel, Switzerland.
Novartis Biomedical Research, Cambridge, MA, USA.
出版信息
Cell Chem Biol. 2025 Jul 17;32(7):955-968.e13. doi: 10.1016/j.chembiol.2025.06.005. Epub 2025 Jul 9.
Aberrant NLRP3 (NACHT-, leucine-rich repeat [LRR]- and pyrin domain [PYD]- containing protein 3) inflammasome activation is linked to many inflammatory diseases, driving the search for therapeutics inhibiting this pathway. NEK7 is proposed to mediate NLRP3 inflammasome assembly and activation by bridging adjacent NLRP3 subunits. Hence, reduction of NEK7 protein may block NLRP3 activation. We identified NK7-902, a potent and selective cereblon (CRBN) glue degrader of NEK7. NK7-902 degraded NEK7 in human immune cells and whole blood. However, full NEK7 degradation completely blocked NLRP3-dependent interleukin-1β (IL-1β) release in vitro only in certain donors and experimental conditions. Unlike most CRBN glue degraders, NK7-902 effectively degraded NEK7 in murine cells and inhibited IL-1β release in mouse in vivo. By contrast, oral administration of NK7-902 in cynomolgus monkey caused long-lasting NEK7 degradation but only transiently blocked IL-1β in blood. These findings suggest NEK7 contributes to but is not absolutely required for NLRP3 activation in monkeys and humans.
异常的NLRP3（含NACHT、富含亮氨酸重复序列[LRR]和吡啉结构域[PYD]的蛋白3）炎性小体激活与许多炎症性疾病相关，这推动了对抑制该途径的治疗方法的探索。有人提出NEK7通过连接相邻的NLRP3亚基来介导NLRP3炎性小体的组装和激活。因此，降低NEK7蛋白水平可能会阻断NLRP3的激活。我们鉴定出了NK7-902，一种强效且选择性的NEK7的脑啡肽（CRBN）胶水降解剂。NK7-902可在人类免疫细胞和全血中降解NEK7。然而，完全降解NEK7仅在某些供体和实验条件下才能在体外完全阻断NLRP3依赖性白细胞介素-1β（IL-1β）的释放。与大多数CRBN胶水降解剂不同，NK7-902能在鼠细胞中有效降解NEK7，并在小鼠体内抑制IL-1β的释放。相比之下，在食蟹猴中口服NK7-902会导致NEK7长期降解，但仅能短暂阻断血液中的IL-1β。这些发现表明，在猴子和人类中，NEK7对NLRP3激活有作用，但并非绝对必需。
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