Journal Article

DKFZ-2025-01335

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Covalent Targeting Leads to the Development of a LIMK1 Isoform-Selective Inhibitor.

Mandel, S. ; Hanke, T. ; Prendiville, N. ; Baena-Nuevo, M. ; Berger, L. M. ; Farges, F. ; Schwalm, M. P.DKFZ* ; Berger, B.-T. ; Kraemer, A. ; Elson, L. ; Saraswati, H. ; Abdul Azeez, K. R. ; Dederer, V. ; Mathea, S. ; Corrionero, A. ; Alfonso, P. ; Keller, S. ; Gstaiger, M. ; Krause, D. S.DKFZ* ; Müller, S.DKFZ* ; Röhm, S. ; Knapp, S.DKFZ*

2025
ACS Washington, DC

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.

Note: 2025 Jul 24;68(14):15026-15049

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Frankfurt (FM01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Chemical Reactions ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; Index Chemicus ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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