PDGF dimer binds two receptors simultaneously

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Homo sapiens
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PDGF dimer binds two receptors simultaneously. The receptors dimerise on ligand binding and undergo conformational change which is key to receptor autophosphorylation (reviewed in Heldin et al, 1998). PDGFRA and PDGFRB activity can be inhibited by binding to type I and type II tyrosine kinase inhibitors (reviewed in Roskoski, 2018). Type I inhibitors such as crenolanib, avripatinib and pazopanib, bind to the active conformation of the receptor, while type II inhibitors like imatinib, sorafenib and others bind to the inactive conformation (Gril et al, 2013; Wang et al, 2014; Mathias et al, 2015; Meliau et al, 2017; Lombardo et al, 2004; Chen et al, 2006; Matsui et al, 2008; Liu et al, 2011; Hilberg et al, 2008; Hilberg et al, 2017; Wilhelm et al, 2002; Strumberg et al, 2005; Mendel et al, 2003; Roskoski, 2007). PDGFRA signaling can also be inhibited by the monoclonal antibody olaratumab, which interferes with binding of AA, BB and CC ligand to the receptor (Gerber et al, 2012; Loizos et al, 2005; Matei et al, 2006; Russell et al, 2010; Stock et al, 2007).

Literature References
PubMed ID Title Journal Year
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Chen, Z, Lee, FY, Bhalla, KN, Wu, J

Mol. Pharmacol. 2006
21251937 Inhibition of PDGF, TGF-β, and Abl signaling and reduction of liver fibrosis by the small molecule Bcr-Abl tyrosine kinase antagonist Nilotinib

Liu, Y, Wang, Z, Kwong, SQ, Lui, ELH, Friedman, SL, Li, FR, Lam, RWC, Zhang, GC, Zhang, H, Ye, T

J. Hepatol. 2011
29408302 The role of small molecule platelet-derived growth factor receptor (PDGFR) inhibitors in the treatment of neoplastic disorders

Roskoski, R

Pharmacol. Res. 2018
23583652 Pazopanib inhibits the activation of PDGFRβ-expressing astrocytes in the brain metastatic microenvironment of breast cancer cells

Gril, B, Palmieri, D, Qian, Y, Anwar, T, Liewehr, DJ, Steinberg, SM, Andreu, Z, Masana, D, Fernández, P, Steeg, PS, Vidal-Vanaclocha, F

Am. J. Pathol. 2013
9739761 Signal transduction via platelet-derived growth factor receptors

Heldin, CH, Ostman, A, Rönnstrand, L

Biochim Biophys Acta 1998
17604334 Platelet-derived growth factor receptor-alpha: a novel therapeutic target in human hepatocellular cancer

Stock, P, Monga, D, Tan, X, Micsenyi, A, Loizos, N, Monga, SP

Mol. Cancer Ther. 2007
18559524 BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy

Hilberg, F, Roth, GJ, Krssak, M, Kautschitsch, S, Sommergruber, W, Tontsch-Grunt, U, Garin-Chesa, P, Bader, G, Zoephel, A, Quant, J, Heckel, A, Rettig, WJ

Cancer Res. 2008
17943726 E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition

Matsui, J, Yamamoto, Y, Funahashi, Y, Tsuruoka, A, Watanabe, T, Wakabayashi, T, Uenaka, T, Asada, M

Int J Cancer 2008
25328409 Crenolanib, a PDGFR inhibitor, suppresses lung cancer cell proliferation and inhibits tumor growth in vivo

Wang, P, Song, L, Ge, H, Jin, P, Jiang, Y, Hu, W, Geng, N

Onco Targets Ther 2014
16331269 Autocrine activation of PDGFRalpha promotes the progression of ovarian cancer

Matei, D, Emerson, RE, Lai, YC, Baldridge, LA, Rao, J, Yiannoutsos, C, Donner, DD

Oncogene 2006
12369853 BAY 43-9006: preclinical data

Wilhelm, S, Chien, DS

Curr. Pharm. Des. 2002
15615512 Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays

Lombardo, LJ, Lee, FY, Chen, P, Norris, D, Barrish, JC, Behnia, K, Castaneda, S, Cornelius, LA, Das, J, Doweyko, AM, Fairchild, C, Hunt, JT, Inigo, I, Johnston, K, Kamath, A, Kan, D, Klei, H, Marathe, P, Pang, S, Peterson, R, Pitt, S, Schieven, GL, Schmidt, RJ, Tokarski, J, Wen, ML, Wityak, J, Borzilleri, RM

J. Med. Chem. 2004
12538485 In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship

Mendel, DB, Laird, AD, Xin, X, Louie, SG, Christensen, JG, Li, G, Schreck, RE, Abrams, TJ, Ngai, TJ, Lee, LB, Murray, LJ, Carver, J, Chan, E, Moss, KG, Haznedar, JO, Sukbuntherng, J, Blake, RA, Sun, L, Tang, C, Miller, T, Shirazian, S, McMahon, G, Cherrington, JM

Clin. Cancer Res. 2003
25597754 The FLT3 and PDGFR inhibitor crenolanib is a substrate of the multidrug resistance protein ABCB1 but does not inhibit transport function at pharmacologically relevant concentrations

Mathias, TJ, Natarajan, K, Shukla, S, Doshi, KA, Singh, ZN, Ambudkar, SV, Baer, MR

Invest New Drugs 2015
22933705 Stromal platelet-derived growth factor receptor α (PDGFRα) provides a therapeutic target independent of tumor cell PDGFRα expression in lung cancer xenografts

Gerber, DE, Gupta, P, Dellinger, MT, Toombs, JE, Peyton, M, Duignan, I, Malaby, J, Bailey, T, Burns, C, Brekken, RA, Loizos, N

Mol. Cancer Ther. 2012
29263244 Triple Angiokinase Inhibitor Nintedanib Directly Inhibits Tumor Cell Growth and Induces Tumor Shrinkage via Blocking Oncogenic Receptor Tyrosine Kinases

Hilberg, F, Tontsch-Grunt, U, Baum, A, Le, AT, Doebele, RC, Lieb, S, Gianni, D, Voss, T, Garin-Chesa, P, Haslinger, C, Kraut, N

J. Pharmacol. Exp. Ther. 2018
17367763 Sunitinib: a VEGF and PDGF receptor protein kinase and angiogenesis inhibitor

Roskoski, R

Biochem. Biophys. Res. Commun. 2007
28435517 Inhibition of the platelet-derived growth factor receptor beta (PDGFRB) using gene silencing, crenolanib besylate, or imatinib mesylate hampers the malignant phenotype of mesothelioma cell lines

Melaiu, O, Catalano, C, De Santi, C, Cipollini, M, Figlioli, G, Pellè, L, Barone, E, Evangelista, M, Guazzelli, A, Boldrini, L, Sensi, E, Bonotti, A, Foddis, R, Cristaudo, A, Mutti, L, Fontanini, G, Gemignani, F, Landi, S

Genes Cancer 2017
16474853 Preclinical and clinical development of the oral multikinase inhibitor sorafenib in cancer treatment

Strumberg, D

Drugs Today 2005
20813817 Targeting the {alpha} receptor for platelet-derived growth factor as a primary or combination therapy in a preclinical model of prostate cancer skeletal metastasis

Russell, MR, Liu, Q, Fatatis, A

Clin. Cancer Res. 2010
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