TY - JOUR
T1 - Development and Characterization of Type I, Type II, and Type III LIM-Kinase Chemical Probes
AU - Hanke, Thomas
AU - Mathea, Sebastian
AU - Woortman, Julia
AU - Salah, Eidarus
AU - Berger, Benedict Tilman
AU - Tumber, Anthony
AU - Kashima, Risa
AU - Hata, Akiko
AU - Kuster, Bernhard
AU - Müller, Susanne
AU - Knapp, Stefan
N1 - Publisher Copyright:
© 2022 American Chemical Society.
PY - 2022/10/13
Y1 - 2022/10/13
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85138948500
U2 - 10.1021/acs.jmedchem.2c01106
DO - 10.1021/acs.jmedchem.2c01106
M3 - Article
C2 - 36136092
AN - SCOPUS:85138948500
SN - 0022-2623
VL - 65
SP - 13264
EP - 13287
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 19
ER -
