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  • br Introduction The discoidin domain

    2019-07-10


    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 Zoniporide dihydrochloride what 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]. Imatinib (STI-571) is a first-line tyrosine kinase inhibitor (TKI) targeted at breakpoint cluster region-Abelson kinase (ABL) for the treatment of chronic myeloid leukemia (CML) [26]. As a type II inhibitor, imatinib achieves significant selectivity by binding to an inactive DFG-out conformation (DFG, Asp-Phe-Gly) of the kinase domain [27]. A chemical proteomics study recently identified DDR1 as a secondary target of imatinib, leading to the suggestion that DDR1 inhibition may also contribute to the effectiveness of the treatment [28], particularly as activation of DDR1 is known to block p53-mediated apoptosis [29]. Further characterization of this interaction revealed imatinib to be a potent inhibitor of DDR1, as were the second-generation TKIs nilotinib and dasatinib [30]. Moreover, dasatinib may have potential to treat squamous cell lung cancer in patients harboring oncogenic mutations in DDR2 [20]. Imatinib also rescues mouse models of fibrosis [31], [32] similarly to DDR1 deficiency [25], although a connection between these effects has yet to be proven. Ponatinib is a third-generation TKI developed for the treatment of CML patients with resistance to imatinib [33], [34]. It was selected primarily to circumvent the steric hindrance introduced by the ABL T315I “gatekeeper” mutation and has proven to be a more potent but considerably less selective inhibitor than imatinib [30]. Finally, the inhibitor DDR1-IN-1 was designed to a similar pharmacophore model as these multi-targeted type II kinase inhibitors but has been recently reported as a highly selective pharmacological probe for DDR1-dependent signal transduction [35]. Such inhibitors will be highly valuable to investigate further the complex roles of DDR1 in both normal and pathobiology. In addition, more selective compounds are likely to offer improved Zoniporide dihydrochloride what safety profiles for potential clinical indications outside oncology. While crystal structures of DDR1 and DDR2 have revealed the molecular basis for extracellular collagen interaction [5], [36], a structural description of the kinase domain fold is lacking. Here, we present the crystal structures of the kinase domain of human DDR1 in complexes with the inhibitors imatinib and ponatinib, as well as structural comparisons to the selective inhibitor DDR1-IN-1. The structures reveal differences to ABL in both the shape and the sequence of the ATP pocket that can be exploited for the design of DDR1-specific inhibitors.