Details of Drug Off-Target (DOT)

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

• DOT Name: Platelet-derived growth factor receptor alpha (PDGFRA)
• Synonyms: PDGF-R-alpha; PDGFR-alpha; EC 2.7.10.1; Alpha platelet-derived growth factor receptor; Alpha-type platelet-derived growth factor receptor; CD140 antigen-like family member A; CD140a antigen; Platelet-derived growth factor alpha receptor; Platelet-derived growth factor receptor 2; PDGFR-2; CD antigen CD140a
• Gene Name: PDGFRA
• Related Disease:
  Gastrointestinal stromal tumour
  Polyps, multiple and recurrent inflammatory fibroid, gastrointestinal
  Congenital heart disease
  Isolated cleft palate
• UniProt ID: PGFRA_HUMAN
• PDB ID: 1GQ5; 5GRN; 5K5X; 6A32; 6JOI; 6JOJ; 6JOK; 6JOL; 7LBF; 7RAM
• EC Number: 2.7.10.1
• Pfam ID: PF07679 ; PF07714
• Sequence:
  MGTSHPAFLVLGCLLTGLSLILCQLSLPSILPNENEKVVQLNSSFSLRCFGESEVSWQYP
  MSEEESSDVEIRNEENNSGLFVTVLEVSSASAAHTGLYTCYYNHTQTEENELEGRHIYIY
  VPDPDVAFVPLGMTDYLVIVEDDDSAIIPCRTTDPETPVTLHNSEGVVPASYDSRQGFNG
  TFTVGPYICEATVKGKKFQTIPFNVYALKATSELDLEMEALKTVYKSGETIVVTCAVFNN
  EVVDLQWTYPGEVKGKGITMLEEIKVPSIKLVYTLTVPEATVKDSGDYECAARQATREVK
  EMKKVTISVHEKGFIEIKPTFSQLEAVNLHEVKHFVVEVRAYPPPRISWLKNNLTLIENL
  TEITTDVEKIQEIRYRSKLKLIRAKEEDSGHYTIVAQNEDAVKSYTFELLTQVPSSILDL
  VDDHHGSTGGQTVRCTAEGTPLPDIEWMICKDIKKCNNETSWTILANNVSNIITEIHSRD
  RSTVEGRVTFAKVEETIAVRCLAKNLLGAENRELKLVAPTLRSELTVAAAVLVLLVIVII
  SLIVLVVIWKQKPRYEIRWRVIESISPDGHEYIYVDPMQLPYDSRWEFPRDGLVLGRVLG
  SGAFGKVVEGTAYGLSRSQPVMKVAVKMLKPTARSSEKQALMSELKIMTHLGPHLNIVNL
  LGACTKSGPIYIITEYCFYGDLVNYLHKNRDSFLSHHPEKPKKELDIFGLNPADESTRSY
  VILSFENNGDYMDMKQADTTQYVPMLERKEVSKYSDIQRSLYDRPASYKKKSMLDSEVKN
  LLSDDNSEGLTLLDLLSFTYQVARGMEFLASKNCVHRDLAARNVLLAQGKIVKICDFGLA
  RDIMHDSNYVSKGSTFLPVKWMAPESIFDNLYTTLSDVWSYGILLWEIFSLGGTPYPGMM
  VDSTFYNKIKSGYRMAKPDHATSEVYEIMVKCWNSEPEKRPSFYHLSEIVENLLPGQYKK
  SYEKIHLDFLKSDHPAVARMRVDSDNAYIGVTYKNEEDKLKDWEGGLDEQRLSADSGYII
  PLPDIDPVPEEEDLGKRNRHSSQTSEESAIETGSSSSTFIKREDETIEDIDMMDDIGIDS
  SDLVEDSFL
• Function: Tyrosine-protein kinase that acts as a cell-surface receptor for PDGFA, PDGFB and PDGFC and plays an essential role in the regulation of embryonic development, cell proliferation, survival and chemotaxis. Depending on the context, promotes or inhibits cell proliferation and cell migration. Plays an important role in the differentiation of bone marrow-derived mesenchymal stem cells. Required for normal skeleton development and cephalic closure during embryonic development. Required for normal development of the mucosa lining the gastrointestinal tract, and for recruitment of mesenchymal cells and normal development of intestinal villi. Plays a role in cell migration and chemotaxis in wound healing. Plays a role in platelet activation, secretion of agonists from platelet granules, and in thrombin-induced platelet aggregation. Binding of its cognate ligands - homodimeric PDGFA, homodimeric PDGFB, heterodimers formed by PDGFA and PDGFB or homodimeric PDGFC -leads to the activation of several signaling cascades; the response depends on the nature of the bound ligand and is modulated by the formation of heterodimers between PDGFRA and PDGFRB. Phosphorylates PIK3R1, PLCG1, and PTPN11. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate, mobilization of cytosolic Ca(2+) and the activation of protein kinase C. Phosphorylates PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, and thereby mediates activation of the AKT1 signaling pathway. Mediates activation of HRAS and of the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. Promotes activation of STAT family members STAT1, STAT3 and STAT5A and/or STAT5B. Receptor signaling is down-regulated by protein phosphatases that dephosphorylate the receptor and its down-stream effectors, and by rapid internalization of the activated receptor.
• Tissue Specificity: Detected in platelets (at protein level). Widely expressed. Detected in brain, fibroblasts, smooth muscle, heart, and embryo. Expressed in primary and metastatic colon tumors and in normal colon tissue.
• KEGG Pathway:
  EGFR tyrosine ki.se inhibitor resistance (hsa01521)
  MAPK sig.ling pathway (hsa04010)
  Ras sig.ling pathway (hsa04014)
  Rap1 sig.ling pathway (hsa04015)
  Calcium sig.ling pathway (hsa04020)
  Phospholipase D sig.ling pathway (hsa04072)
  Endocytosis (hsa04144)
  PI3K-Akt sig.ling pathway (hsa04151)
  Focal adhesion (hsa04510)
  Gap junction (hsa04540)
  JAK-STAT sig.ling pathway (hsa04630)
  Regulation of actin cytoskeleton (hsa04810)
  Human cytomegalovirus infection (hsa05163)
  Pathways in cancer (hsa05200)
  MicroR.s in cancer (hsa05206)
  Glioma (hsa05214)
  Prostate cancer (hsa05215)
  Melanoma (hsa05218)
  Central carbon metabolism in cancer (hsa05230)
  Choline metabolism in cancer (hsa05231)
• Reactome Pathway:
  Downstream signal transduction (R-HSA-186763)
  Signaling by PDGF (R-HSA-186797)
  Constitutive Signaling by Aberrant PI3K in Cancer (R-HSA-2219530)
  RAF/MAP kinase cascade (R-HSA-5673001)
  PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558)
  Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants (R-HSA-9673767)
  Signaling by PDGFRA extracellular domain mutants (R-HSA-9673770)
  Imatinib-resistant PDGFR mutants (R-HSA-9674396)
  Sunitinib-resistant PDGFR mutants (R-HSA-9674401)
  Regorafenib-resistant PDGFR mutants (R-HSA-9674403)
  Sorafenib-resistant PDGFR mutants (R-HSA-9674404)
  PDGFR mutants bind TKIs (R-HSA-9674428)
  PIP3 activates AKT signaling (R-HSA-1257604)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Gastrointestinal stromal tumour	DIS6TJYS	Definitive	Autosomal dominant	[1]
Polyps, multiple and recurrent inflammatory fibroid, gastrointestinal	DIS5YYEV	Strong	Autosomal dominant	[2]
Congenital heart disease	DISQBA23	Limited	Autosomal dominant	[1]
Isolated cleft palate	DISV80CD	Limited	Unknown	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Platelet-derived growth factor receptor alpha (PDGFRA).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Platelet-derived growth factor receptor alpha (PDGFRA).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Platelet-derived growth factor receptor alpha (PDGFRA).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Platelet-derived growth factor receptor alpha (PDGFRA).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Platelet-derived growth factor receptor alpha (PDGFRA).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Platelet-derived growth factor receptor alpha (PDGFRA).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Platelet-derived growth factor receptor alpha (PDGFRA).	[11]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Platelet-derived growth factor receptor alpha (PDGFRA).	[8]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Platelet-derived growth factor receptor alpha (PDGFRA).	[12]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Platelet-derived growth factor receptor alpha (PDGFRA).	[11]
Imatinib	DM7RJXL	Approved	Imatinib decreases the expression of Platelet-derived growth factor receptor alpha (PDGFRA).	[17]
Ardeparin	DMYRX8B	Approved	Ardeparin decreases the expression of Platelet-derived growth factor receptor alpha (PDGFRA).	[18]
Sodium chloride	DMM3950	Approved	Sodium chloride increases the expression of Platelet-derived growth factor receptor alpha (PDGFRA).	[19]
Vismodegib	DM5IXKQ	Approved	Vismodegib decreases the expression of Platelet-derived growth factor receptor alpha (PDGFRA).	[20]
Masitinib	DMRSNEU	Phase 3	Masitinib decreases the activity of Platelet-derived growth factor receptor alpha (PDGFRA).	[21]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Platelet-derived growth factor receptor alpha (PDGFRA).	[22]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Platelet-derived growth factor receptor alpha (PDGFRA).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Platelet-derived growth factor receptor alpha (PDGFRA).	[24]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Platelet-derived growth factor receptor alpha (PDGFRA).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Platelet-derived growth factor receptor alpha (PDGFRA).	[26]
PMID25656651-Compound-5	DMAI95U	Patented	PMID25656651-Compound-5 decreases the activity of Platelet-derived growth factor receptor alpha (PDGFRA).	[27]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Platelet-derived growth factor receptor alpha (PDGFRA).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Platelet-derived growth factor receptor alpha (PDGFRA).	[29]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Platelet-derived growth factor receptor alpha (PDGFRA).	[30]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Platelet-derived growth factor receptor alpha (PDGFRA).	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Platelet-derived growth factor receptor alpha (PDGFRA).	[9]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Platelet-derived growth factor receptor alpha (PDGFRA).	[13]
Folic acid	DMEMBJC	Approved	Folic acid affects the methylation of Platelet-derived growth factor receptor alpha (PDGFRA).	[14]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the phosphorylation of Platelet-derived growth factor receptor alpha (PDGFRA).	[15]
Sorafenib	DMS8IFC	Approved	Sorafenib decreases the phosphorylation of Platelet-derived growth factor receptor alpha (PDGFRA).	[16]

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