Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTWL9TY)

• DTT Name: LIM domain kinase-1 (LIMK-1)
• Synonyms: LIMK-1; LIMK
• Gene Name: LIMK1
• DTT Type: Literature-reported target; [1]
• BioChemical Class: Kinase
• UniProt ID: LIMK1_HUMAN
• TTD ID: T70840
• EC Number: EC 2.7.11.1
• Sequence:
  MRLTLLCCTWREERMGEEGSELPVCASCGQRIYDGQYLQALNADWHADCFRCCDCSASLS
  HQYYEKDGQLFCKKDYWARYGESCHGCSEQITKGLVMVAGELKYHPECFICLTCGTFIGD
  GDTYTLVEHSKLYCGHCYYQTVVTPVIEQILPDSPGSHLPHTVTLVSIPASSHGKRGLSV
  SIDPPHGPPGCGTEHSHTVRVQGVDPGCMSPDVKNSIHVGDRILEINGTPIRNVPLDEID
  LLIQETSRLLQLTLEHDPHDTLGHGLGPETSPLSSPAYTPSGEAGSSARQKPVLRSCSID
  RSPGAGSLGSPASQRKDLGRSESLRVVCRPHRIFRPSDLIHGEVLGKGCFGQAIKVTHRE
  TGEVMVMKELIRFDEETQRTFLKEVKVMRCLEHPNVLKFIGVLYKDKRLNFITEYIKGGT
  LRGIIKSMDSQYPWSQRVSFAKDIASGMAYLHSMNIIHRDLNSHNCLVRENKNVVVADFG
  LARLMVDEKTQPEGLRSLKKPDRKKRYTVVGNPYWMAPEMINGRSYDEKVDVFSFGIVLC
  EIIGRVNADPDYLPRTMDFGLNVRGFLDRYCPPNCPPSFFPITVRCCDLDPEKRPSFVKL
  EHWLETLRMHLAGHLPLGPQLEQLDRGFWETYRRGESGLPAHPEVPD
• Function: 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). Serine/threonine-protein kinase that plays an essential role in the regulation of actin filament dynamics.
• 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 DTT

5 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PMID19831390C14	DMIECOF	Discovery agent	N.A.	Investigative	[2]
PMID22902653C30	DMXDTPL	Discovery agent	N.A.	Investigative	[3]
PMID22902653C31	DMWVTAE	Discovery agent	N.A.	Investigative	[3]
PMID22902653C35	DMLVKPG	Discovery agent	N.A.	Investigative	[3]
RKI-1447	DMGTAWC	Discovery agent	N.A.	Investigative	[1]

References

• [1] Pyridylthiazole-based ureas as inhibitors of Rho associated protein kinases (ROCK1 and 2). Medchemcomm. 2012 Jun 1;3(6):699-709.
• [2] Novel class of LIM-kinase 2 inhibitors for the treatment of ocular hypertension and associated glaucoma. J Med Chem. 2009 Nov 12;52(21):6515-8.
• [3] Modulation of cofilin phosphorylation by inhibition of the Lim family kinases. Bioorg Med Chem Lett. 2012 Sep 15;22(18):5995-8.