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. 2025 Jul 17;32(7):955-968.e13.
doi: 10.1016/j.chembiol.2025.06.005. Epub 2025 Jul 9.

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

Aude Sylvain  1 , Natacha Stoehr  1 , Fupeng Ma  2 , Artiom Cernijenko  2 , Martin Schröder  1 , Maryam Khoshouei  1 , Melanie Vogelsanger  1 , Michel Schoenboerner  1 , Ashley Burke  2 , Pasupuleti Rao  2 , Jonathan M Solomon  2 , Joshiawa Paulk  2 , Lei Xu  2 , Janet Dawson  1 , Damien Begue  1 , Peggy Lefeuvre  1 , Erik Ahrne  1 , Andreas Hofmann  1 , Callum J Dickson  2 , Philip Arabin  1 , Alfred Zimmerlin  1 , Michael Kiffe  1 , Mirjam Froehlicher  1 , Theresa Boersig  1 , Azeddine Elhajouji  1 , Murielle Brichet  1 , Suchithra Menon  2 , Shanming Liu  2 , Matthias Mueller  1 , Charles A Wartchow  3 , James Lin  3 , Yamel Cardona Gloria  4 , Sabine Dickhöfer  4 , Alexander N R Weber  5 , Tatjana Welzel  6 , Jasmin Kuemmerle-Deschner  7 , Christopher J Farady  1 , Robert Pulz  1 , Frederic Bornancin  1 , Dennis L Buckley  8 , Zuni I Bassi  9
Affiliations

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

Aude Sylvain et al. Cell Chem Biol. .

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.

Keywords: CRBN; NEK7; NLRP3 inflammasome; inflammation; molecular glue degrader.

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Conflict of interest statement

Declaration of interests All authors except Y.C.G., S.D., A.N.R.W., T.W., and J.K.-D. are past or current employees and shareholders of Novartis. Some of the authors have patents related to this work: US2020/16143 (F.M and A.C.) and US2020/361898 (C.J.F.). J.K.-D. received speaker fees, honoraria, and research grant support from Novartis and SOBI. T.W. has given invited talks for Novartis without a personal honorarium.

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