%0 Journal Article
%A Mandel, Sebastian
%A Hanke, Thomas
%A Prendiville, Niall
%A Baena-Nuevo, María
%A Berger, Lena Marie
%A Farges, Frederic
%A Schwalm, Martin Peter
%A Berger, Benedict-Tilman
%A Kraemer, Andreas
%A Elson, Lewis
%A Saraswati, Hayuningbudi
%A Abdul Azeez, Kamal R
%A Dederer, Verena
%A Mathea, Sebastian
%A Corrionero, Ana
%A Alfonso, Patricia
%A Keller, Sabrina
%A Gstaiger, Matthias
%A Krause, Daniela S
%A Müller, Susanne
%A Röhm, Sandra
%A Knapp, Stefan
%T Covalent Targeting Leads to the Development of a LIMK1 Isoform-Selective Inhibitor.
%J Journal of medicinal chemistry
%V 68
%N 14
%@ 0095-9065
%C Washington, DC
%I ACS
%M DKFZ-2025-01335
%P 15026-15049
%D 2025
%Z 2025 Jul 24;68(14):15026-15049
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40598933
%R 10.1021/acs.jmedchem.5c01204
%U https://inrepo02.dkfz.de/record/302795