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Review
. 2022 Jun 30;11(13):2090.
doi: 10.3390/cells11132090.

LIM Kinases, Promising but Reluctant Therapeutic Targets: Chemistry and Preclinical Validation In Vivo

Rayan Berabez  1 , Sylvain Routier  1 , Hélène Bénédetti  2 , Karen Plé  1 , Béatrice Vallée  2
Affiliations
Review

LIM Kinases, Promising but Reluctant Therapeutic Targets: Chemistry and Preclinical Validation In Vivo

Rayan Berabez et al. Cells. .

Abstract

LIM Kinases are important actors in the regulation of cytoskeleton dynamics by controlling microtubule and actin filament turnover. The signaling pathways involving LIM kinases for actin filament remodeling are well established. They are downstream effectors of small G proteins of the Rho-GTPases family and have become promising targets for the treatment of several major diseases because of their position at the lower end of these signaling cascades. Cofilin, which depolymerizes actin filaments, is the best-known substrate of these enzymes. The phosphorylation of cofilin to its inactive form by LIM kinases avoids actin filament depolymerization. The balance between phosphorylated and non-phosphorylated cofilin is thought to play an important role in tumor cell invasion and metastasis. Since 2006, many small molecules have been developed for LIMK inhibition, and in this review article, we will discuss the structure-activity relationships of the few inhibitor families that have been tested in vivo on different pathological models.

Keywords: LIMK; in vivo preclinical validation; medicinal chemistry.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
LIM Kinase signaling pathway.
Figure 2
Figure 2
Chronological development of LIM Kinase inhibitors tested in vivo.
Figure 3
Figure 3
Structure and activity of BMS compounds: selective LIMK inhibitors (blue), cytotoxic LIMK inhibitors (green), and cytotoxic compounds with no LIMK activity (red).
Scheme 1
Scheme 1
Phenyl ring Structure activity studies.
Scheme 2
Scheme 2
Structural optimization of Compound 11.
Figure 4
Figure 4
Lead LIMK2 inhibitors, Lexicon Pharmaceuticals 2009.
Figure 5
Figure 5
SAR optimization of compound 20.
Figure 6
Figure 6
LX7101 modulation by Amakem Therapeutics.
Figure 7
Figure 7
Progress toward LIMK inhibition.
Figure 8
Figure 8
Optimized LIMK1 inhibitors.
Figure 9
Figure 9
Pyr 1, O-benzyl derivative (31), and 9-OH metabolite (32).
Figure 10
Figure 10
AWL-II-38.3 (A) and T56-LIMKi (B).
Figure 11
Figure 11
Damnacanthal.
See this image and copyright information in PMC

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References

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Grants and funding

This research was funded by the Centre National de la Recherche Scientifique, the Ministère de l’Enseignement Supérieur et de la Recherche: University of Orleans, La Ligue contre le Cancer, the French Association Neurofibromatoses et Recklinghausen, the French Agence Nationale de la Recherche grant number: ANR-19-CE18-0016-02, and the region Centre Val de Loire.

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