Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTFN95D)

• DTT Name: PAK-1 protein kinase (PAK1)
• Synonyms: p65-PAK; p21-activated kinase 1; Serine/threonine-protein kinase PAK 1; PAK-1; Alpha-PAK
• Gene Name: PAK1
• DTT Type: Literature-reported target; [1]
• BioChemical Class: Kinase
• UniProt ID: PAK1_HUMAN
• TTD ID: T37961
• EC Number: EC 2.7.11.1
• Sequence:
  MSNNGLDIQDKPPAPPMRNTSTMIGAGSKDAGTLNHGSKPLPPNPEEKKKKDRFYRSILP
  GDKTNKKKEKERPEISLPSDFEHTIHVGFDAVTGEFTGMPEQWARLLQTSNITKSEQKKN
  PQAVLDVLEFYNSKKTSNSQKYMSFTDKSAEDYNSSNALNVKAVSETPAVPPVSEDEDDD
  DDDATPPPVIAPRPEHTKSVYTRSVIEPLPVTPTRDVATSPISPTENNTTPPDALTRNTE
  KQKKKPKMSDEEILEKLRSIVSVGDPKKKYTRFEKIGQGASGTVYTAMDVATGQEVAIKQ
  MNLQQQPKKELIINEILVMRENKNPNIVNYLDSYLVGDELWVVMEYLAGGSLTDVVTETC
  MDEGQIAAVCRECLQALEFLHSNQVIHRDIKSDNILLGMDGSVKLTDFGFCAQITPEQSK
  RSTMVGTPYWMAPEVVTRKAYGPKVDIWSLGIMAIEMIEGEPPYLNENPLRALYLIATNG
  TPELQNPEKLSAIFRDFLNRCLEMDVEKRGSAKELLQHQFLKIAKPLSSLTPLIAAAKEA
  TKNNH
• Function: Can directly phosphorylate BAD and protects cells against apoptosis. Activated by interaction with CDC42 and RAC1. Functions as GTPase effector that links the Rho-related GTPases CDC42 and RAC1 to the JNK MAP kinase pathway. Phosphorylates and activates MAP2K1, and thereby mediates activation of downstream MAP kinases. Involved in the reorganization of the actin cytoskeleton, actin stress fibers and of focal adhesion complexes. Phosphorylates the tubulin chaperone TBCB and thereby plays a role in the regulation of microtubule biogenesis and organization of the tubulin cytoskeleton. Plays a role in the regulation of insulin secretion in response to elevated glucose levels. Part of a ternary complex that contains PAK1, DVL1 and MUSK that is important for MUSK-dependent regulation of AChR clustering during the formation of the neuromuscular junction (NMJ). Activity is inhibited in cells undergoing apoptosis, potentially due to binding of CDC2L1 and CDC2L2. Phosphorylates MYL9/MLC2. Phosphorylates RAF1 at 'Ser-338' and 'Ser-339' resulting in: activation of RAF1, stimulation of RAF1 translocation to mitochondria, phosphorylation of BAD by RAF1, and RAF1 binding to BCL2. Phosphorylates SNAI1 at 'Ser-246' promoting its transcriptional repressor activity by increasing its accumulation in the nucleus. In podocytes, promotes NR3C2 nuclear localization. Required for atypical chemokine receptor ACKR2-induced phosphorylation of LIMK1 and cofilin (CFL1) and for the up-regulation of ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation. In synapses, seems to mediate the regulation of F-actin cluster formation performed by SHANK3, maybe through CFL1 phosphorylation and inactivation. Plays a role in RUFY3-mediated facilitating gastric cancer cells migration and invasion. In response to DNA damage, phosphorylates MORC2 which activates its ATPase activity and facilitates chromatin remodeling. Protein kinase involved in intracellular signaling pathways downstream of integrins and receptor-type kinases that plays an important role in cytoskeleton dynamics, in cell adhesion, migration, proliferation, apoptosis, mitosis, and in vesicle-mediated transport processes.
• KEGG Pathway:
  MAPK signaling pathway (hsa04010)
  ErbB signaling pathway (hsa04012)
  Ras signaling pathway (hsa04014)
  cAMP signaling pathway (hsa04024)
  Chemokine signaling pathway (hsa04062)
  Axon guidance (hsa04360)
  Hippo signaling pathway - multiple species (hsa04392)
  Focal adhesion (hsa04510)
  C-type lectin receptor signaling pathway (hsa04625)
  Natural killer cell mediated cytotoxicity (hsa04650)
  T cell receptor signaling pathway (hsa04660)
  Fc gamma R-mediated phagocytosis (hsa04666)
  Regulation of actin cytoskeleton (hsa04810)
  Epithelial cell signaling in Helicobacter pylori infection (hsa05120)
  Pathogenic Escherichia coli infection (hsa05130)
  Salmonella infection (hsa05132)
  Human immunodeficiency virus 1 infection (hsa05170)
  Proteoglycans in cancer (hsa05205)
  Renal cell carcinoma (hsa05211)
• Reactome Pathway:
  Regulation of actin dynamics for phagocytic cup formation (R-HSA-2029482)
  FCERI mediated MAPK activation (R-HSA-2871796)
  DSCAM interactions (R-HSA-376172)
  CD28 dependent Vav1 pathway (R-HSA-389359)
  EPHB-mediated forward signaling (R-HSA-3928662)
  Ephrin signaling (R-HSA-3928664)
  Sema3A PAK dependent Axon repulsion (R-HSA-399954)
  Activation of RAC1 (R-HSA-428540)
  Signal transduction by L1 (R-HSA-445144)
  Smooth Muscle Contraction (R-HSA-445355)
  VEGFR2 mediated vascular permeability (R-HSA-5218920)
  CD209 (DC-SIGN) signaling (R-HSA-5621575)
  RHO GTPases activate PKNs (R-HSA-5625740)
  RHO GTPases Activate ROCKs (R-HSA-5627117)
  RHO GTPases activate PAKs (R-HSA-5627123)
  MAPK6/MAPK4 signaling (R-HSA-5687128)
  G beta (R-HSA-8964616)
  CDC42 GTPase cycle (R-HSA-9013148)
  RAC1 GTPase cycle (R-HSA-9013149)
  RAC2 GTPase cycle (R-HSA-9013404)
  RHOQ GTPase cycle (R-HSA-9013406)
  RHOH GTPase cycle (R-HSA-9013407)
  RHOJ GTPase cycle (R-HSA-9013409)
  RHOU GTPase cycle (R-HSA-9013420)
  RAC3 GTPase cycle (R-HSA-9013423)
  RHOV GTPase cycle (R-HSA-9013424)
  Generation of second messenger molecules (R-HSA-202433)

Molecular Interaction Atlas (MIA) of This DTT

3 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Il-94	DMPNQ27	Discovery agent	N.A.	Investigative	[1]
PMID20005102C1	DMMESBW	Discovery agent	N.A.	Investigative	[2]
RKI-1447	DMGTAWC	Discovery agent	N.A.	Investigative	[3]

References

• [1] PAK1: A Therapeutic Target for Cancer Treatment. ACS Med Chem Lett. 2013 Mar 19;4(5):431-2.
• [2] 2,3,5-Trisubstituted pyridines as selective AKT inhibitors. Part II: Improved drug-like properties and kinase selectivity from azaindazoles. Bioorg Med Chem Lett. 2010 Jan 15;20(2):679-83.
• [3] Pyridylthiazole-based ureas as inhibitors of Rho associated protein kinases (ROCK1 and 2). Medchemcomm. 2012 Jun 1;3(6):699-709.