Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFZ8MZ0)

• DOT Name: LIM domain kinase 1 (LIMK1)
• Synonyms: LIMK-1; EC 2.7.11.1
• Gene Name: LIMK1
• UniProt ID: LIMK1_HUMAN
• PDB ID: 3S95; 5HVJ; 5HVK; 5L6W; 5NXC; 6WLY; 7ATS; 7ATU; 7B8W; 8AAU
• EC Number: 2.7.11.1
• Pfam ID: PF00412 ; PF00595 ; PF07714
• Sequence:
  MRLTLLCCTWREERMGEEGSELPVCASCGQRIYDGQYLQALNADWHADCFRCCDCSASLS
  HQYYEKDGQLFCKKDYWARYGESCHGCSEQITKGLVMVAGELKYHPECFICLTCGTFIGD
  GDTYTLVEHSKLYCGHCYYQTVVTPVIEQILPDSPGSHLPHTVTLVSIPASSHGKRGLSV
  SIDPPHGPPGCGTEHSHTVRVQGVDPGCMSPDVKNSIHVGDRILEINGTPIRNVPLDEID
  LLIQETSRLLQLTLEHDPHDTLGHGLGPETSPLSSPAYTPSGEAGSSARQKPVLRSCSID
  RSPGAGSLGSPASQRKDLGRSESLRVVCRPHRIFRPSDLIHGEVLGKGCFGQAIKVTHRE
  TGEVMVMKELIRFDEETQRTFLKEVKVMRCLEHPNVLKFIGVLYKDKRLNFITEYIKGGT
  LRGIIKSMDSQYPWSQRVSFAKDIASGMAYLHSMNIIHRDLNSHNCLVRENKNVVVADFG
  LARLMVDEKTQPEGLRSLKKPDRKKRYTVVGNPYWMAPEMINGRSYDEKVDVFSFGIVLC
  EIIGRVNADPDYLPRTMDFGLNVRGFLDRYCPPNCPPSFFPITVRCCDLDPEKRPSFVKL
  EHWLETLRMHLAGHLPLGPQLEQLDRGFWETYRRGESGLPAHPEVPD
• Function: Serine/threonine-protein kinase that plays an essential role in the regulation of actin filament dynamics. Acts downstream of several Rho family GTPase signal transduction pathways. Activated by upstream kinases including ROCK1, PAK1 and PAK4, which phosphorylate LIMK1 on a threonine residue located in its activation loop. LIMK1 subsequently phosphorylates and inactivates the actin binding/depolymerizing factors cofilin-1/CFL1, cofilin-2/CFL2 and destrin/DSTN, thereby preventing the cleavage of filamentous actin (F-actin), and stabilizing the actin cytoskeleton. In this way LIMK1 regulates several actin-dependent biological processes including cell motility, cell cycle progression, and differentiation. Phosphorylates TPPP on serine residues, thereby promoting microtubule disassembly. Stimulates axonal outgrowth and may be involved in brain development ; [Isoform 3]: Has a dominant negative effect on actin cytoskeletal changes. Required for atypical chemokine receptor ACKR2-induced phosphorylation of cofilin (CFL1).
• Tissue Specificity: Highest expression in both adult and fetal nervous system. Detected ubiquitously throughout the different regions of adult brain, with highest levels in the cerebral cortex. Expressed to a lesser extent in heart and skeletal muscle.
• KEGG Pathway:
  Axon guidance (hsa04360)
  Fc gamma R-mediated phagocytosis (hsa04666)
  Regulation of actin cytoskeleton (hsa04810)
  Yersinia infection (hsa05135)
  Human immunodeficiency virus 1 infection (hsa05170)
• Reactome Pathway:
  EPHB-mediated forward signaling (R-HSA-3928662)
  Sema3A PAK dependent Axon repulsion (R-HSA-399954)
  Sema4D induced cell migration and growth-cone collapse (R-HSA-416572)
  RHO GTPases Activate ROCKs (R-HSA-5627117)
  RHO GTPases activate PAKs (R-HSA-5627123)
  Regulation of actin dynamics for phagocytic cup formation (R-HSA-2029482)

Molecular Interaction Atlas (MIA) of This DOT

4 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of LIM domain kinase 1 (LIMK1).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of LIM domain kinase 1 (LIMK1).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of LIM domain kinase 1 (LIMK1).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of LIM domain kinase 1 (LIMK1).	[18]

14 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of LIM domain kinase 1 (LIMK1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of LIM domain kinase 1 (LIMK1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of LIM domain kinase 1 (LIMK1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of LIM domain kinase 1 (LIMK1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of LIM domain kinase 1 (LIMK1).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of LIM domain kinase 1 (LIMK1).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of LIM domain kinase 1 (LIMK1).	[8]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of LIM domain kinase 1 (LIMK1).	[9]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of LIM domain kinase 1 (LIMK1).	[10]
Acocantherin	DM7JT24	Approved	Acocantherin decreases the expression of LIM domain kinase 1 (LIMK1).	[11]
Ximelegatran	DMU8ANS	Approved	Ximelegatran decreases the expression of LIM domain kinase 1 (LIMK1).	[12]
Tacrolimus	DMZ7XNQ	Approved	Tacrolimus increases the expression of LIM domain kinase 1 (LIMK1).	[13]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of LIM domain kinase 1 (LIMK1).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of LIM domain kinase 1 (LIMK1).	[16]

References

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• [3] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
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• [11] Ouabain impairs cell migration, and invasion and alters gene expression of human osteosarcoma U-2 OS cells. Environ Toxicol. 2017 Nov;32(11):2400-2413. doi: 10.1002/tox.22453. Epub 2017 Aug 10.
• [12] Organized migration of epithelial cells requires control of adhesion and protrusion through Rho kinase effectors. Am J Physiol Gastrointest Liver Physiol. 2007 Mar;292(3):G806-17. doi: 10.1152/ajpgi.00333.2006. Epub 2006 Nov 30.
• [13] Calcineurin is an important factor involved in glucose uptake in human adipocytes. Mol Cell Biochem. 2018 Aug;445(1-2):157-168. doi: 10.1007/s11010-017-3261-0. Epub 2018 Jan 27.
• [14] Resveratrol enhances ultraviolet B-induced cell death through nuclear factor-kappaB pathway in human epidermoid carcinoma A431 cells. Biochem Biophys Res Commun. 2009 Jun 26;384(2):215-20. doi: 10.1016/j.bbrc.2009.04.100. Epub 2009 May 3.
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• [16] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [17] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [18] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.