Proteomics

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Covalent targeting leads to the development of LIMK1 isoform-selective inhibitors

ABSTRACT: SM311 is a covalent LIMK1 inhibitor. To verify the specificity of SM311 towards LIMK1, a chemoproteomic competition experiment was set up with a biotin adduct of SM311, namely SM429. This adduct was immobilised on Streptactin beads and used to enrich proteins binding to SM429. Preincubation with an excess of SM311 was used as control to outcompete and block the binding of SM429. In the competition setup we show that LIMK1 is depleted if SM311 is added in excess but also identified two additional kinase off-targets that required further profiling.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Matthias Gstaiger  

LAB HEAD: Matthias Gstaiger

PROVIDER: PXD063179 | Pride | 2025-08-04

REPOSITORIES: Pride

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Dataset's files

Source:
Action DRS
20250415_125115_Ex20240822_sabkeller_LIMK1_15min_Lib.sne Other
20250415_134946_Ex20240822_sabkeller_LIMK1_15min_Lib_Report.tsv Tabular
240826_LU1_sabkell_Ex20240822_DIA1.raw Raw
240826_LU1_sabkell_Ex20240822_DIA10.raw Raw
240826_LU1_sabkell_Ex20240822_DIA11.raw Raw
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Publications

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  ...[more]

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