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@ARTICLE{Mandel:302795,
author = {S. Mandel and T. Hanke and N. Prendiville and M.
Baena-Nuevo and L. M. Berger and F. Farges and M. P.
Schwalm$^*$ and B.-T. Berger and A. Kraemer and L. Elson and
H. Saraswati and K. R. Abdul Azeez and V. Dederer and S.
Mathea and A. Corrionero and P. Alfonso and S. Keller and M.
Gstaiger and D. S. Krause$^*$ and S. Müller$^*$ and S.
Röhm and S. Knapp$^*$},
title = {{C}ovalent {T}argeting {L}eads to the {D}evelopment of a
{LIMK}1 {I}soform-{S}elective {I}nhibitor.},
journal = {Journal of medicinal chemistry},
volume = {68},
number = {14},
issn = {0095-9065},
address = {Washington, DC},
publisher = {ACS},
reportid = {DKFZ-2025-01335},
pages = {15026-15049},
year = {2025},
note = {2025 Jul 24;68(14):15026-15049},
abstract = {Selectivity for closely related isoforms of protein kinases
is a major challenge in the design of drugs and chemical
probes. Covalent targeting of unique cysteines is a
potential strategy to achieve selectivity for highly
conserved binding sites. Here, we used a pan-LIMK inhibitor
to selectively probe LIMK1 over LIMK2 by targeting the
LIMK1-specific cysteine C349 located in the glycine-rich
loop region. Binding kinetics of both noncovalent and
covalent LIMK inhibitors were investigated, and the fast
on-rate and small size of type-I inhibitors were used in the
design of a covalent LIMK1 inhibitor. The developed
cell-active, isoform-selective LIMK1 inhibitor showed
excellent proteome-wide selectivity in pull-down assays,
enabling studies of LIMK1 isoform-selective functions in
cellular model systems and providing a versatile chemical
tool for studies of the LIMK signaling pathway.},
cin = {FM01},
ddc = {610},
cid = {I:(DE-He78)FM01-20160331},
pnm = {899 - ohne Topic (POF4-899)},
pid = {G:(DE-HGF)POF4-899},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:40598933},
doi = {10.1021/acs.jmedchem.5c01204},
url = {https://inrepo02.dkfz.de/record/302795},
}