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  • Three kinase inhibitors dasatinib type I imatinib type

    2019-08-20

    Three kinase inhibitors dasatinib (type I), imatinib (type II) and nilotinib (type II), identified initially as inhibitors of tyrosine kinase BCR-ABL, were found to target DDRs in a chemical proteomic profiling study (Bantscheff et al., 2007, Hantschel et al., 2008). These tyrosine kinase inhibitors block DDR1 and DDR2 kinase activity in biochemical assays and prevent collagen-mediated DDR tyrosine autophosphorylation in Sodium salicylate reviews overexpressing these two receptors (Day et al., 2008). Although dasatinib inhibits DDR1 at very low concentrations, it is not selective for DDR1, thus increasing the chances of off-target effects when used in vivo and limiting the analysis of DDR1-mediated specific signaling. Recently, two studies reported the identification of novel and selective DDR1 inhibitors. Screening of a library of approximately 2000 compounds originally designed to inhibit BCR-ABL and other RTKs allowed the identification of pyrazolopyrimidine derivatives as selective DDR1 inhibitors. In particular, two of these pyrazolopyrimidine derivatives have high affinity for DDR1 but not for other 455 kinases tested, and inhibit the proliferation of cancer cells expressing high levels of DDR1 (Gao et al., 2013). Sodium salicylate reviews However, whether these derivatives are type I or type II inhibitors remains to be determined. A second study, aimed to identify selective type II DDR1 inhibitors, identified DDR1-IN-1 as a potent DDR1 inhibitor able to inhibit DDR1 autophosphorylation in cells at concentrations in the micromolar range (Kim et al., 2013). A crystal structure of the DDR1 kinase domain together with DDR1-IN-1 confirmed that this is a type II inhibitor, and mutagenesis studies revealed that a mutation in the hinge region of DDR1 close to the gate-keeper residue confers resistance to this type II inhibitor (Kim et al., 2013). Thus, this mutant may be useful in establishing off-target effects of DDR1 type II inhibitors in a cellular context. Although promising, DDR1-IN-1 did not significantly block proliferation of DDR1-expressing cancer cell lines, suggesting that blocking DDR1 kinase activity alone may not be sufficient to inhibit and/or halt unwanted cell proliferation (Kim et al., 2013). Nevertheless, the identification of selective DDR inhibitors is expected to advance our understanding of DDR-mediated physiological and pathological effects in vivo and to provide new tools for the treatment of DDR-mediated diseases.
    Conclusions
    Acknowledgments
    Introduction The discoidin domain receptors (DDRs), DDR1 and DDR2, are unique among the receptor tyrosine kinases (RTKs) in being activated by interaction with the extracellular matrix [1], [2]. Binding to triple-helical collagen is mediated by the receptor extracellular domains that include an N-terminal discoidin (DS) domain, a DS-like domain and a short juxtamembrane (JM) region [3], [4], [5]. A single transmembrane helix links to the cytoplasmic domain, where a larger JM region precedes the catalytic C-terminal kinase domain. Both DDRs form constitutive dimers making them unusual among RTKs, which typically dimerize only upon activation [6], [7], [8]. DDRs regulate extracellular matrix remodeling, as well as cell adhesion, proliferation and migration [9]. DDR1 is expressed mainly in epithelial cells where it plays an important role in mammary gland development [10], whereas mesenchymal expression of DDR2 promotes bone growth, as suggested by dwarfism in DDR2 knockout mice [11]. DDR kinases are linked to the progression of various human diseases, including fibrotic disorders, atherosclerosis and cancer [9], [12], [13]. Significantly, they are identified as indicators of poor prognosis in ovarian, breast and lung cancer [14], [15], [16]. DDR1 overexpression is associated with increased cell survival and invasion in hepatocellular carcinomas, pituitary adenoma and prostate cancer [17], [18], [19], whereas DDR2 is mutated in squamous cell lung cancers [20] and contributes to breast cancer metastasis [21]. The promise of DDR kinases as a therapeutic target has been demonstrated by DDR1 knockdown that has been shown to reduce metastatic activity in lung cancer models [22], slow the development of atherosclerosis [13] and impede the development of fibrotic disorders [23], [24], [25].