A cereblon-based glue degrader of NEK7 regulates NLRP3 inflammasome in a context-dependent manner

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Chemical Biology Pub Date : 2025-07-17 DOI:10.1016/j.chembiol.2025.06.005

Aude Sylvain , Natacha Stoehr , Fupeng Ma , Artiom Cernijenko , Martin Schröder , Maryam Khoshouei , Melanie Vogelsanger , Michel Schoenboerner , Ashley Burke , Pasupuleti Rao , Jonathan M. Solomon , Joshiawa Paulk , Lei Xu , Janet Dawson , Damien Begue , Peggy Lefeuvre , Erik Ahrne , Andreas Hofmann , Callum J. Dickson , Philip Arabin , Zuni I. Bassi

{"title":"A cereblon-based glue degrader of NEK7 regulates NLRP3 inflammasome in a context-dependent manner","authors":"Aude Sylvain , Natacha Stoehr , Fupeng Ma , Artiom Cernijenko , Martin Schröder , Maryam Khoshouei , Melanie Vogelsanger , Michel Schoenboerner , Ashley Burke , Pasupuleti Rao , Jonathan M. Solomon , Joshiawa Paulk , Lei Xu , Janet Dawson , Damien Begue , Peggy Lefeuvre , Erik Ahrne , Andreas Hofmann , Callum J. Dickson , Philip Arabin , Zuni I. Bassi","doi":"10.1016/j.chembiol.2025.06.005","DOIUrl":null,"url":null,"abstract":"<div><div>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 <em>in vitro</em> 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 <em>in vivo</em>. 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.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 7","pages":"Pages 955-968.e13"},"PeriodicalIF":6.6000,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Chemical Biology","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2451945625002004","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

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.

Abstract Image

查看原文本刊更多论文

基于小脑的NEK7胶降解剂以上下文依赖的方式调节NLRP3炎性体

异常的NLRP3 （NACHT-，富含亮氨酸的重复序列[LRR]-和pyrin结构域[PYD]-含蛋白3）炎性体激活与许多炎症性疾病有关，推动了对抑制该途径的治疗方法的研究。NEK7被认为通过桥接邻近的NLRP3亚基介导NLRP3炎症小体的组装和激活。因此，NEK7蛋白的减少可能会阻断NLRP3的激活。我们鉴定出了NK7-902，一种有效的、选择性的NEK7的小脑（CRBN）胶降解剂。NK7-902在人免疫细胞和全血中降解NEK7。然而，完全的NEK7降解完全阻断了nlrp3依赖性白细胞介素-1β (IL-1β)的体外释放，仅在某些供体和实验条件下。与大多数CRBN胶降解剂不同，NK7-902有效降解小鼠细胞中的NEK7，并抑制小鼠体内IL-1β的释放。相比之下，食蟹猴口服NK7-902导致NEK7长期降解，但仅短暂阻断血液中的IL-1β。这些发现表明，在猴子和人类中，NEK7对NLRP3的激活起作用，但不是绝对必需的。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Cell Chemical Biology Biochemistry, Genetics and Molecular Biology-Molecular Medicine

CiteScore

14.70

自引率

2.30%

发文量

143

期刊介绍： Cell Chemical Biology, a Cell Press journal established in 1994 as Chemistry & Biology, focuses on publishing crucial advances in chemical biology research with broad appeal to our diverse community, spanning basic scientists to clinicians. Pioneering investigations at the chemistry-biology interface, the journal fosters collaboration between these disciplines. We encourage submissions providing significant conceptual advancements of broad interest across chemical, biological, clinical, and related fields. Particularly sought are articles utilizing chemical tools to perturb, visualize, and measure biological systems, offering unique insights into molecular mechanisms, disease biology, and therapeutics.