TY  - JOUR
AU  - Mandel, Sebastian
AU  - Hanke, Thomas
AU  - Prendiville, Niall
AU  - Baena-Nuevo, María
AU  - Berger, Lena Marie
AU  - Farges, Frederic
AU  - Schwalm, Martin Peter
AU  - Berger, Benedict-Tilman
AU  - Kraemer, Andreas
AU  - Elson, Lewis
AU  - Saraswati, Hayuningbudi
AU  - Abdul Azeez, Kamal R
AU  - Dederer, Verena
AU  - Mathea, Sebastian
AU  - Corrionero, Ana
AU  - Alfonso, Patricia
AU  - Keller, Sabrina
AU  - Gstaiger, Matthias
AU  - Krause, Daniela S
AU  - Müller, Susanne
AU  - Röhm, Sandra
AU  - Knapp, Stefan
TI  - Covalent Targeting Leads to the Development of a LIMK1 Isoform-Selective Inhibitor.
JO  - Journal of medicinal chemistry
VL  - 68
IS  - 14
SN  - 0095-9065
CY  - Washington, DC
PB  - ACS
M1  - DKFZ-2025-01335
SP  - 15026-15049
PY  - 2025
N1  - 2025 Jul 24;68(14):15026-15049
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:40598933
DO  - DOI:10.1021/acs.jmedchem.5c01204
UR  - https://inrepo02.dkfz.de/record/302795
ER  -