Open AccessDevelopment and Characterization of Type I, Type II, and Type III LIM-Kinase Chemical Probes
Author(s) -
Thomas Hanke,
Sebastian Mathea,
Julia Rechenberger,
E. Salah,
BenedictTilman Berger,
Anthony Tumber,
Risa Kashima,
Akiko Hata,
Bernhard Küster,
Susanne Müller,
Stefan Knapp
Publication year - 2022
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.2c01106
Subject(s) - chemistry , allosteric regulation , kinase , phenotypic screening , small molecule , lead compound , biochemistry , phenotype , in vitro , enzyme , gene
LIMKs are important regulators of actin and microtubule dynamics, and they play essential roles in many cellular processes. Deregulation of LIMKs has been linked to the development of diverse diseases, including cancers and cognitive disabilities, but well-characterized inhibitors known as chemical probes are still lacking. Here, we report the characterization of three highly selective LIMK1/2 inhibitors covering all canonical binding modes (type I/II/III) and the structure-based design of the type II/III inhibitors. Characterization of these chemical probes revealed a low nanomolar affinity for LIMK1/2, and all inhibitors 1 ( LIMKi3 ; type I), 48 ( TH470 ; type II), and 15 ( TH257 ; type III) showed excellent selectivity in a comprehensive scanMAX kinase selectivity panel. Phosphoproteomics revealed remarkable differences between type I and type II inhibitors compared with the allosteric inhibitor 15 . In phenotypic assays such as neurite outgrowth models of fragile X-chromosome, 15 showed promising activity, suggesting the potential application of allosteric LIMK inhibitors treating this orphan disease.