TY  - JOUR
AU  - Sylvain, Aude
AU  - Stoehr, Natacha
AU  - Ma, Fupeng
AU  - Cernijenko, Artiom
AU  - Schröder, Martin
AU  - Khoshouei, Maryam
AU  - Vogelsanger, Melanie
AU  - Schoenboerner, Michel
AU  - Burke, Ashley
AU  - Rao, Pasupuleti
AU  - Solomon, Jonathan M
AU  - Paulk, Joshiawa
AU  - Xu, Lei
AU  - Dawson, Janet
AU  - Begue, Damien
AU  - Lefeuvre, Peggy
AU  - Ahrne, Erik
AU  - Hofmann, Andreas
AU  - Dickson, Callum J
AU  - Arabin, Philip
AU  - Zimmerlin, Alfred
AU  - Kiffe, Michael
AU  - Froehlicher, Mirjam
AU  - Boersig, Theresa
AU  - Elhajouji, Azeddine
AU  - Brichet, Murielle
AU  - Menon, Suchithra
AU  - Liu, Shanming
AU  - Mueller, Matthias
AU  - Wartchow, Charles A
AU  - Lin, James
AU  - Gloria, Yamel Cardona
AU  - Dickhöfer, Sabine
AU  - Weber, Alexander
AU  - Welzel, Tatjana
AU  - Kuemmerle-Deschner, Jasmin
AU  - Farady, Christopher J
AU  - Pulz, Robert
AU  - Bornancin, Frederic
AU  - Buckley, Dennis L
AU  - Bassi, Zuni I
TI  - A cereblon-based glue degrader of NEK7 regulates NLRP3 inflammasome in a context-dependent manner.
JO  - Cell chemical biology
VL  - 32
IS  - 7
SN  - 2451-9456
CY  - Amsterdam
PB  - Elsevier
M1  - DKFZ-2025-01374
SP  - 955-968.e13
PY  - 2025
N1  - 2025 Jul 17;32(7):955-968.e13
AB  - 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.
KW  - CRBN (Other)
KW  - NEK7 (Other)
KW  - NLRP3 inflammasome (Other)
KW  - inflammation (Other)
KW  - molecular glue degrader (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:40639372
DO  - DOI:10.1016/j.chembiol.2025.06.005
UR  - https://inrepo02.dkfz.de/record/302834
ER  -