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Last update 08 May 2025

LIMK2

Last update 08 May 2025

Basic Info

Synonyms

LIM domain kinase 2, LIMK-2, LIMK2

Introduction

Serine/threonine-protein kinase that plays an essential role in the regulation of actin filament dynamics (PubMed:10436159, PubMed:11018042). Acts downstream of several Rho family GTPase signal transduction pathways (PubMed:10436159, PubMed:11018042). Involved in astral microtubule organization and mitotic spindle orientation during early stages of mitosis by mediating phosphorylation of TPPP (PubMed:22328514). Displays serine/threonine-specific phosphorylation of myelin basic protein and histone (MBP) in vitro (PubMed:8537403). Suppresses ciliogenesis via multiple pathways; phosphorylation of CFL1, suppression of directional trafficking of ciliary vesicles to the ciliary base, and by facilitating YAP1 nuclear localization where it acts as a transcriptional corepressor of the TEAD4 target genes AURKA and PLK1 (PubMed:25849865).

Drugs associated with LIMK2

LIMKi-3

Target

LIMK1 x LIMK2

Mechanism

LIMK1 inhibitors [+1]

Active Org.

University of Cardiff [+1]

Originator Org.

University of Cardiff

Active Indication

Fragile X Syndrome [+1]

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

TH-257

Target

LIMK1 x LIMK2

Mechanism

LIMK1 inhibitors [+1]

Active Org.

Johann Wolfgang Goethe-Universität Frankfurt am Main [+1]

Originator Org.

University of Cardiff

Active Indication

Fragile X Syndrome [+1]

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

TH-470

Target

LIMK1 x LIMK2

Mechanism

LIMK1 inhibitors [+1]

Active Org.

Johann Wolfgang Goethe-Universität Frankfurt am Main

Originator Org.

Johann Wolfgang Goethe-Universität Frankfurt am Main

Active Indication

Fragile X Syndrome

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with LIMK2

100 Translational Medicine associated with LIMK2

0 Patents (Medical) associated with LIMK2

250

Literatures (Medical) associated with LIMK2

01 Apr 2025·Computational Biology and Chemistry

Unveiling novel type 1 inhibitors for targeting LIM kinase 2 (LIMK2) for cancer therapeutics: An integrative pharmacoinformatics approach

Article

Author: Jeyakanthan, Jeyaraman ; Hemavathy, Nagarajan ; Umashankar, Vetrivel

LIMK2 is crucial in regulating actin cytoskeleton dynamics, significantly contributing to cancer cell proliferation, invasion, and metastasis. Inhibitors like LIMKi3 effectively suppress LIMK2 kinase activity by directly affecting actin polymerization and preventing the formation of structures like filopodia and lamellipodia, which are typical of motile cancer cells. By modulating these actin dynamics, LIMKi3 inhibits cancer cell migration and invasion, reducing the potential for metastasis. Thus, this study aims to explore potential anti-cancer therapeutic LIMK2 inhibitors with properties resembling LIMKi3. Henceforth, molecular docking was utilized in this study to comprehend the ATP mimetic binding mode of LIMKi3, followed by Pharmacophore-based virtual screening to identify small molecules resembling LIMKi3. In addition, molecular dynamics simulations were performed to explore the dynamic behavior of LIMK2 and potential inhibitors. Further, network analysis and binding free energy calculations were implemented to comprehensively assess the interactions between the compounds and LIMK2. In molecular docking, LIMKi3 demonstrated an ATP mimetic hinge binding mode with hydrogen bonds at Ile408. Among the screened compounds (NCI300395, ChemDiv-8020-2508, and ChemDiv-7997-0024), three displayed "ADRH" pharmacophoric features like LIMKi3, with favorable ADMET properties, higher binding affinity, and significant hydrogen bond interactions at Ile408. LIMK2-inhibitor complexes showed lower RMSD than LIMK2-LIMKi3, indicating higher equilibrium by identified compounds. Protein-drug Complexes exhibited significant inter-domain correlation in N-lobe residues of LIMK2, including conserved β3, αC, and Hinge residues. Binding free energy analysis ranked LIMK2-NCI300395 highest, followed by LIMK2-ChemDiv-7997-0024 and LIMK2-ChemDiv-8020-2508, highlighting their potential as effective LIMK2-targeting compounds. Hence, this study emphasizes LIMKi3's significance and identifies potential candidates (NCI300395, ChemDiv-7997-0024, and ChemDiv-8020-2508) for developing cancer therapeutics targeting LIMK2. These findings open avenues for further investigations into the complex interplay between cytoskeletal dynamics and cancer progression.

01 Mar 2025·The Journal of Prevention of Alzheimer's Disease

Multi-omics analysis of druggable genes to facilitate Alzheimer's disease therapy: A multi-cohort machine learning study

Article

Author: Wang, Xiaochuan ; Luo, Yong ; Hu, Jichang

BACKGROUNDThe swift rise in the prevalence of Alzheimer's disease (AD) alongside its significant societal and economic impact has created a pressing demand for effective interventions and treatments. However, there are no available treatments that can modify the progression of the disease.METHODSEight AD brain tissues datasets and three blood datasets were obtained. Consensus clustering was utilized as a method to discern the various subtypes of AD. Then, module genes were screened using weighted correlation network analysis (WGCNA). Furthermore, screening hub genes was conducted through machine-learning analyses. Finally, A comprehensive analysis using a systematic approach to druggable genome-wide Mendelian randomization (MR) was conducted.RESULTSTwo AD subclasses were identified, namely cluster.A and cluster.B. The levels of gamma secretase activity, beta secretase activity, and amyloid-beta 42 were found to be significantly elevated in patients classified within cluster A when compared to those in cluster B. Furthermore, by utilizing the differentially expressed genes shared among these clusters, along with identifying druggable genes and applying WGCNA to these subtypes, we were able to develop a scoring system referred to as DG.score. This scoring system has demonstrated remarkable predictive capability for AD when evaluated against multiple datasets. Besides, A total of 30 distinct genes that may serve as potential drug targets for AD were identified across at least one of the datasets investigated, whether derived from brain samples or blood analyses. Among the identified genes, three specific candidates that are considered druggable (LIMK2, MAPK8, and NDUFV2) demonstrated significant expression levels in both blood and brain tissues. Furthermore, our research also revealed a potential association between the levels of LIMK2 and concentrations of CSF Aβ (OR 1.526 (1.155-2.018)), CSF p-tau (OR 1.106 (1.024-01.196)), and hippocampal size (OR 0.831 (0.702-0.948)).CONCLUSIONSThis study provides a notable advancement to the existing literature by offering genetic evidence that underscores the potential therapeutic advantages of focusing on the druggable gene LIMK2 in the treatment of AD. This insight not only contributes to our understanding of AD but also guides future drug discovery efforts.

11 Feb 2025·Journal of Biomolecular Structure and Dynamics

Harnessing allosteric inhibition: prioritizing LIMK2 inhibitors for targeted cancer therapy through pharmacophore-based virtual screening and essential molecular dynamics

Article

Author: Subramaniyan, Sneha ; Vetrivel, Umashankar ; Jeyakanthan, Jeyaraman ; Hemavathy, Nagarajan ; Rangaswamy, Raghu

The therapeutic potential of small molecule kinase inhibitors in cancer treatment is well recognized. However, achieving selectivity remains a formidable challenge, primarily due to the structural similarity of ATP binding pockets among kinases. Allosteric inhibition, which involves targeting binding pockets beyond the ATP-binding site, provides a promising alternative to overcome this challenge. In this study, a meticulous approach was implemented to prioritize type 3 inhibitors for LIMK2, employing a range of techniques including Molecular Dynamics (MD) simulations, e-pharmacophore-guided High Throughput Virtual Screening (HTVS), MM/GBSA and ADMETox analyses, Density Functional Theory (DFT) calculations, and MM/PBSA investigations. The e-pharmacophore model identifies a hypothesis featuring five essential pharmacophoric elements (RRRAH). Through virtual screening of the ZINC compound database, we identified only five compounds that align with all four pharmacophoric features: ZINC1044382792, ZINC1433610865, ZINC1044109145, ZINC952869440, and ZINC490621334. These compounds not only exhibit higher binding affinity but also demonstrate favorable ADME/Tox profiles. Molecular dynamics simulations underscore the stability of hydrogen bond interactions with critical cryptic LIMK2 pocket residues, Asp469 and Arg474, only for two compounds: ZINC143361086 and ZINC1044382792. These compounds also exhibit superior occupancy interactions, as indicated by HOMO-LUMO analysis. Additionally, binding free energy calculations highlight the significant affinities of these two compounds when complexed with LIMK2: -83.491 ± 1.230 kJ/mol and -90.122 ± 1.248 kJ/mol for ZINC1044382792 and ZINC1433610862, respectively. Hence, this comprehensive investigation identifies ZINC1433610862 and ZINC1044382792 as prospective hits, representing promising leads for targeting LIMK2 in cancer therapeutics.Communicated by Ramaswamy H. Sarma.

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LIMK2

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