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@ARTICLE{Sylvain:302834,
author = {A. Sylvain and N. Stoehr and F. Ma and A. Cernijenko and M.
Schröder and M. Khoshouei and M. Vogelsanger and M.
Schoenboerner and A. Burke and P. Rao and J. M. Solomon and
J. Paulk and L. Xu and J. Dawson and D. Begue and P.
Lefeuvre and E. Ahrne and A. Hofmann and C. J. Dickson and
P. Arabin and A. Zimmerlin and M. Kiffe and M. Froehlicher
and T. Boersig and A. Elhajouji and M. Brichet and S. Menon
and S. Liu and M. Mueller and C. A. Wartchow and J. Lin and
Y. C. Gloria and S. Dickhöfer and A. Weber$^*$ and T.
Welzel and J. Kuemmerle-Deschner and C. J. Farady and R.
Pulz and F. Bornancin and D. L. Buckley and Z. I. Bassi},
title = {{A} cereblon-based glue degrader of {NEK}7 regulates
{NLRP}3 inflammasome in a context-dependent manner.},
journal = {Cell chemical biology},
volume = {32},
number = {7},
issn = {2451-9456},
address = {Amsterdam},
publisher = {Elsevier},
reportid = {DKFZ-2025-01374},
pages = {955-968.e13},
year = {2025},
note = {2025 Jul 17;32(7):955-968.e13},
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 (Other) / NEK7 (Other) / NLRP3 inflammasome (Other) /
inflammation (Other) / molecular glue degrader (Other)},
cin = {TU01},
ddc = {570},
cid = {I:(DE-He78)TU01-20160331},
pnm = {899 - ohne Topic (POF4-899)},
pid = {G:(DE-HGF)POF4-899},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:40639372},
doi = {10.1016/j.chembiol.2025.06.005},
url = {https://inrepo02.dkfz.de/record/302834},
}