Target Information

Target General Infomation
Target ID
T53524
Former ID
TTDC00311
Target Name
Alpha platelet-derived growth factor receptor
Gene Name
PDGFRA
Synonyms
CD140a antigen; PDGF-R-alpha; Platelet-derived growth factor receptor alpha; PDGFRA
Target Type
Successful
Disease Cancer [ICD9: 140-229; ICD10: C00-C96]
Glioblastoma multiforme [ICD9: 191; ICD10: C71]
Gastrointestinal cancers [ICD9: 150-159; ICD10: C15-C26]
Non-small cell lung cancer; Ovarian cancer [ICD9:183; ICD10: C33-C34, C56]
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48]
Soft tissue sarcoma [ICD9: 171; ICD10: C00-D49]
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.
BioChemical Class
Kinase
Target Validation
T53524
UniProt ID
P16234
EC Number
EC 2.7.10.1
Sequence
MGTSHPAFLVLGCLLTGLSLILCQLSLPSILPNENEKVVQLNSSFSLRCFGESEVSWQYP
MSEEESSDVEIRNEENNSGLFVTVLEVSSASAAHTGLYTCYYNHTQTEENELEGRHIYIY
VPDPDVAFVPLGMTDYLVIVEDDDSAIIPCRTTDPETPVTLHNSEGVVPASYDSRQGFNG
TFTVGPYICEATVKGKKFQTIPFNVYALKATSELDLEMEALKTVYKSGETIVVTCAVFNN
EVVDLQWTYPGEVKGKGITMLEEIKVPSIKLVYTLTVPEATVKDSGDYECAARQATREVK
EMKKVTISVHEKGFIEIKPTFSQLEAVNLHEVKHFVVEVRAYPPPRISWLKNNLTLIENL
TEITTDVEKIQEIRYRSKLKLIRAKEEDSGHYTIVAQNEDAVKSYTFELLTQVPSSILDL
VDDHHGSTGGQTVRCTAEGTPLPDIEWMICKDIKKCNNETSWTILANNVSNIITEIHSRD
RSTVEGRVTFAKVEETIAVRCLAKNLLGAENRELKLVAPTLRSELTVAAAVLVLLVIVII
SLIVLVVIWKQKPRYEIRWRVIESISPDGHEYIYVDPMQLPYDSRWEFPRDGLVLGRVLG
SGAFGKVVEGTAYGLSRSQPVMKVAVKMLKPTARSSEKQALMSELKIMTHLGPHLNIVNL
LGACTKSGPIYIITEYCFYGDLVNYLHKNRDSFLSHHPEKPKKELDIFGLNPADESTRSY
VILSFENNGDYMDMKQADTTQYVPMLERKEVSKYSDIQRSLYDRPASYKKKSMLDSEVKN
LLSDDNSEGLTLLDLLSFTYQVARGMEFLASKNCVHRDLAARNVLLAQGKIVKICDFGLA
RDIMHDSNYVSKGSTFLPVKWMAPESIFDNLYTTLSDVWSYGILLWEIFSLGGTPYPGMM
VDSTFYNKIKSGYRMAKPDHATSEVYEIMVKCWNSEPEKRPSFYHLSEIVENLLPGQYKK
SYEKIHLDFLKSDHPAVARMRVDSDNAYIGVTYKNEEDKLKDWEGGLDEQRLSADSGYII
PLPDIDPVPEEEDLGKRNRHSSQTSEESAIETGSSSSTFIKREDETIEDIDMMDDIGIDS
SDLVEDSFL
Drugs and Mode of Action
Drug(s) Olaratumab Drug Info Approved Soft tissue sarcoma [1]
CP-868596 Drug Info Phase 3 Gastrointestinal cancers [2], [3]
E-3810 Drug Info Phase 3 Solid tumours [4], [5]
Famitinib Drug Info Phase 2 Cancer [6], [7]
MEDI-575 Drug Info Phase 2 Glioblastoma multiforme [8]
MP470 Drug Info Phase 2 Solid tumours [9], [10], [11]
XL-820 Drug Info Phase 2 Solid tumours [12]
Olaratumab Drug Info Phase 1 Non-small cell lung cancer; Ovarian cancer [13]
SRI-62-834 Drug Info Discontinued in Phase 2 Solid tumours [14]
CEP-2563 Drug Info Discontinued in Phase 1 Solid tumours [15]
AG1295 Drug Info Terminated Discovery agent [16], [17]
RG-13022 Drug Info Terminated Discovery agent [18]
Inhibitor (1H-indol-2-yl)(5-methoxy-1H-indol-2-yl)methanone Drug Info [19]
(1H-indol-2-yl)(5-phenoxy-1H-indol-2-yl)methanone Drug Info [19]
(1H-indol-2-yl)(6-methoxy-1H-indol-2-yl)methanone Drug Info [19]
(5-fluoro-1H-indol-2-yl)-(1H-indol-2-yl)methanone Drug Info [19]
(5-hydroxy-1H-indol-2-yl)(1H-indol-2-yl)methanone Drug Info [19]
1-Phenyl-1H-benzoimidazol-5-ol Drug Info [20]
1-Phenyl-1H-benzoimidazole Drug Info [20]
3-((E)-Styryl)-quinoline Drug Info [21]
3-(1H-Indol-3-yl)-6,7-dimethoxy-quinoline Drug Info [21]
3-(1H-Indol-3-yl)-quinoline Drug Info [21]
3-(2-Cyclohexyl-ethyl)-6,7-dimethoxy-quinoline Drug Info [21]
3-(3,4-Dichloro-phenyl)-6,7-dimethoxy-quinoline Drug Info [21]
3-(3,4-Difluoro-phenyl)-6,7-dimethoxy-quinoline Drug Info [21]
3-(3,4-Dimethoxy-phenyl)-6,7-dimethoxy-quinoline Drug Info [21]
3-(3-Fluoro-phenyl)-6,7-dimethoxy-quinoline Drug Info [21]
3-(4-Fluoro-phenyl)-6,7-dimethoxy-quinoline Drug Info [21]
3-Benzyloxy-6,7-dimethoxy-quinoline Drug Info [21]
3-Cyclohexylethynyl-6,7-dimethoxy-quinoline Drug Info [21]
3-Cyclopent-1-enyl-6,7-dimethoxy-quinoline Drug Info [21]
3-Cyclopentyl-6,7-dimethoxy-quinoline Drug Info [21]
3-Pyridin-3-yl-quinoline-6,7-diol Drug Info [21]
3-Pyridin-4-yl-quinolin-7-ol Drug Info [22]
3-Pyridin-4-yl-quinoline Drug Info [22]
3-Pyridin-4-yl-quinoline-5,7-diol Drug Info [22]
3-Thiophen-3-yl-quinoline Drug Info [21]
4-(3,4-Dimethoxy-phenoxy)-6,7-dimethoxy-quinoline Drug Info [23]
4-(5-Methoxy-benzoimidazol-1-yl)-phenylamine Drug Info [24]
4-(6,7-Dimethoxy-quinolin-3-yl)-benzoic acid Drug Info [21]
4-(6,7-Dimethoxy-quinolin-3-yl)-phenol Drug Info [21]
4-Benzoimidazol-1-yl-phenylamine Drug Info [20]
5,11-Dimethyl-6H-pyrido[4,3-b]carbazol-9-ol Drug Info [25]
5,6,7-Trimethoxy-3-pyridin-4-yl-quinoline Drug Info [22]
5,7-Dimethoxy-3-pyridin-4-yl-quinoline Drug Info [22]
5,7-Dimethoxy-3-thiophen-3-yl-quinoline Drug Info [21]
5,7-Dimethyl-3-thiophen-3-yl-quinoline Drug Info [21]
5-(6,7-Dimethoxy-quinolin-3-yl)-1H-pyridin-2-one Drug Info [21]
5-Fluoro-3-thiophen-3-yl-quinoline Drug Info [21]
5-Methoxy-1-phenyl-1H-benzoimidazole Drug Info [20]
6,7-Dichloro-3-thiophen-3-yl-quinoline Drug Info [21]
6,7-Difluoro-3-thiophen-3-yl-quinoline Drug Info [21]
6,7-Dimethoxy-3-((E)-styryl)-quinoline Drug Info [21]
6,7-Dimethoxy-3-(2-methoxy-phenyl)-quinoline Drug Info [21]
6,7-Dimethoxy-3-(3-methoxy-phenyl)-quinoline Drug Info [21]
6,7-Dimethoxy-3-(4-methoxy-phenyl)-quinoline Drug Info [21]
6,7-Dimethoxy-3-(4-nitro-phenyl)-quinoline Drug Info [21]
6,7-Dimethoxy-3-p-tolyl-quinoline Drug Info [21]
6,7-Dimethoxy-3-phenyl-quinoline Drug Info [21]
6,7-Dimethoxy-3-phenylethynyl-quinoline Drug Info [21]
6,7-Dimethoxy-3-pyridin-3-yl-quinoline Drug Info [21]
6,7-Dimethoxy-3-pyridin-4-yl-quinoline Drug Info [22]
6,7-Dimethoxy-3-thiophen-2-yl-quinoline Drug Info [21]
6-Methoxy-3-pyridin-4-yl-quinoline Drug Info [22]
6-Methoxy-3-thiophen-3-yl-quinoline Drug Info [21]
7-Chloro-3-pyridin-4-yl-quinoline Drug Info [22]
7-Fluoro-3-thiophen-3-yl-quinoline Drug Info [21]
7-Methoxy-3-pyridin-4-yl-quinoline Drug Info [22]
7-Methoxy-3-thiophen-3-yl-quinoline Drug Info [21]
7-Thiophen-3-yl-[1,3]dioxolo[4,5-g]quinoline Drug Info [21]
AG1295 Drug Info [19]
Benzyl-(6,7-dimethoxy-quinolin-3-yl)-amine Drug Info [21]
Bis-(5-hydroxy-1H-indol-2-yl)-methanone Drug Info [19]
BMS-536924 Drug Info [26]
CEP-2563 Drug Info [27]
compound 8h Drug Info [28]
compound 8h Drug Info [29]
CP-673451 Drug Info [30]
D-65476 Drug Info [31]
Di(1H-indol-2-yl)methanone Drug Info [19]
E-3810 Drug Info [32]
Famitinib Drug Info [6]
JNJ-10198409 Drug Info [33]
PD-0166326 Drug Info [34]
PD-0173952 Drug Info [34]
PD-0173955 Drug Info [34]
PD-0173956 Drug Info [34]
PD-0173958 Drug Info [34]
PD-0179483 Drug Info [34]
PD-0180970 Drug Info [34]
PP121 Drug Info [35]
RG-13022 Drug Info [21]
Ro-4396686 Drug Info [36]
RPR-101511 Drug Info [21]
RPR-108514A Drug Info [37]
SEMAXINIB Drug Info [38]
SRI-62-834 Drug Info [39]
SU-11652 Drug Info [38]
XL-820 Drug Info [40]
Modulator CP-868596 Drug Info
MP470 Drug Info [9], [10]
Olaratumab Drug Info [41]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
DRM DRM Info
Pathways
KEGG Pathway MAPK signaling pathway
Ras signaling pathway
Rap1 signaling pathway
Calcium signaling pathway
Cytokine-cytokine receptor interaction
Endocytosis
PI3K-Akt signaling pathway
Focal adhesion
Gap junction
Regulation of actin cytoskeleton
HTLV-I infection
Pathways in cancer
MicroRNAs in cancer
Glioma
Prostate cancer
Melanoma
Central carbon metabolism in cancer
Choline metabolism in cancer
NetPath Pathway TGF_beta_Receptor Signaling Pathway
PANTHER Pathway Angiogenesis
PDGF signaling pathway
Pathway Interaction Database ATF-2 transcription factor network
PDGFR-alpha signaling pathway
PDGF receptor signaling network
Reactome PIP3 activates AKT signaling
Constitutive Signaling by Aberrant PI3K in Cancer
RAF/MAP kinase cascade
WikiPathways Regulation of Actin Cytoskeleton
Osteoblast Signaling
Focal Adhesion
Organogenesis (Part 2 of 3)
PIP3 activates AKT signaling
Cardiac Progenitor Differentiation
Integrated Pancreatic Cancer Pathway
Allograft Rejection
Signaling Pathways in Glioblastoma
Signaling by PDGF
Angiogenesis
References
REF 12016 FDA drug approvals. Nat Rev Drug Discov. 2017 Feb 2;16(2):73-76. doi: 10.1038/nrd.2017.14.
REF 2(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7882).
REF 3Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800015430)
REF 4ClinicalTrials.gov (NCT02135107) A Double-blind Comparative Study of the Efficacy and Safety of E3810 10mg Once and Twice Daily in Maintenance Therapy for PPI Resistant Gastroesophageal Reflux Disease Patients. U.S. National Institutes of Health.
REF 5(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7649).
REF 6Metabolism and bioactivation of famitinib, a novel inhibitor of receptor tyrosine kinase, in cancer patients. Br J Pharmacol. 2013 Apr;168(7):1687-706.
REF 7(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7886).
REF 8Clinical pipeline report, company report or official report of MedImmune (2011).
REF 9The receptor tyrosine kinase inhibitor amuvatinib (MP470) sensitizes tumor cells to radio- and chemo-therapies in part by inhibiting homologous recombination. Radiother Oncol. 2011 Oct;101(1):59-65.
REF 10Phase 1B study of amuvatinib in combination with five standard cancer therapies in adults with advanced solid tumors. Cancer Chemother Pharmacol. 2014 Jul;74(1):195-204.
REF 11(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7932).
REF 12ClinicalTrials.gov (NCT00570635) A Phase 2 Study of XL820 in Adults With Advanced GIST Resistant to Imatinib and/or Sunitinib. U.S. National Institutes of Health.
REF 13ClinicalTrials.gov (NCT02377752) A Study of Olaratumab in Japanese Participants With Advanced Cancer. U.S. National Institutes of Health.
REF 14Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000818)
REF 15Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007988)
REF 16(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5914).
REF 17Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007894)
REF 18Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000854)
REF 19J Med Chem. 2006 Jun 1;49(11):3101-15.Novel bis(1H-indol-2-yl)methanones as potent inhibitors of FLT3 and platelet-derived growth factor receptor tyrosine kinase.
REF 20J Med Chem. 1998 Dec 31;41(27):5457-65.Structure-activity relationships for 1-phenylbenzimidazoles as selective ATP site inhibitors of the platelet-derived growth factor receptor.
REF 21J Med Chem. 1994 Jul 8;37(14):2129-37.A new series of PDGF receptor tyrosine kinase inhibitors: 3-substituted quinoline derivatives.
REF 22J Med Chem. 1994 Aug 19;37(17):2627-9.5,7-Dimethoxy-3-(4-pyridinyl)quinoline is a potent and selective inhibitor of human vascular beta-type platelet-derived growth factor receptor tyrosine kinase.
REF 23A novel series of 4-phenoxyquinolines: potent and highly selective inhibitors of PDGF receptor autophosphorylation, Bioorg. Med. Chem. Lett. 7(23):2935-2940 (1997).
REF 24J Med Chem. 1999 Jul 1;42(13):2373-82.Structure-activity relationships for 5-substituted 1-phenylbenzimidazoles as selective inhibitors of the platelet-derived growth factor receptor.
REF 25J Med Chem. 2005 Oct 6;48(20):6194-201.Molecular modeling of wild-type and D816V c-Kit inhibition based on ATP-competitive binding of ellipticine derivatives to tyrosine kinases.
REF 26J Med Chem. 2005 Sep 8;48(18):5639-43.Discovery of a (1H-benzoimidazol-2-yl)-1H-pyridin-2-one (BMS-536924) inhibitor of insulin-like growth factor I receptor kinase with in vivo antitumor activity.
REF 27Phase I clinical trial of CEP-2563 dihydrochloride, a receptor tyrosine kinase inhibitor, in patients with refractory solid tumors. Invest New Drugs. 2004 Nov;22(4):449-58.
REF 28Discovery of 5-(arenethynyl) hetero-monocyclic derivatives as potent inhibitors of BCR-ABL including the T315I gatekeeper mutant. Bioorg Med Chem Lett. 2011 Jun 15;21(12):3743-8.
REF 29The design, synthesis, and biological evaluation of potent receptor tyrosine kinase inhibitors. Bioorg Med Chem Lett. 2012 Aug 1;22(15):4979-85.
REF 30Antiangiogenic and antitumor activity of a selective PDGFR tyrosine kinase inhibitor, CP-673,451. Cancer Res. 2005 Feb 1;65(3):957-66.
REF 31Bis(1H-2-indolyl)methanones as a novel class of inhibitors of the platelet-derived growth factor receptor kinase. J Med Chem. 2002 Feb 28;45(5):1002-18.
REF 32E-3810 is a potent dual inhibitor of VEGFR and FGFR that exerts antitumor activity in multiple preclinical models. Cancer Res. 2011 Feb 15;71(4):1396-405. doi: 10.1158/0008-5472.CAN-10-2700. Epub 2011 Jan 6.
REF 33J Med Chem. 2005 Dec 29;48(26):8163-73.(6,7-Dimethoxy-2,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenylamines: platelet-derived growth factor receptor tyrosine kinase inhibitors with broad antiproliferative activity against tumor cells.
REF 34Biochem Pharmacol. 2000 Oct 1;60(7):885-98.Biochemical and cellular effects of c-Src kinase-selective pyrido[2, 3-d]pyrimidine tyrosine kinase inhibitors.
REF 35Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases. Nat Chem Biol. 2008 Nov;4(11):691-9.
REF 36Bioorg Med Chem Lett. 2006 Apr 1;16(7):1950-3. Epub 2006 Feb 3.Biological evaluation of a multi-targeted small molecule inhibitor of tumor-induced angiogenesis.
REF 37The synthesis and SAR of new 4-(N-alkyl-N-phenyl)amino-6,7-dimethoxyquinazolines and 4-(N-alkyl-N-phenyl)aminopyrazolo[3,4-d]pyrimidines, inhibitors of CSF-1R tyrosine kinase activity, Bioorg. Med. Chem. Lett. 7(4):421-424 (1997).
REF 38J Med Chem. 2003 Mar 27;46(7):1116-9.Discovery of 5-[5-fluoro-2-oxo-1,2- dihydroindol-(3Z)-ylidenemethyl]-2,4- dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine kinase.
REF 39Antitumor activity of SRI 62-834, a cyclic ether analog of ET-18-OCH3. Lipids. 1987 Nov;22(11):884-90.
REF 40National Cancer Institute Drug Dictionary (drug id 452042).
REF 41A phase I study of olaratumab, an anti-platelet-derived growth factor receptor alpha (PDGFRalpha) monoclonal antibody, in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2014 Mar;73(3):595-604.

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