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  • Imatinib STI is a first line tyrosine kinase


    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]. SIN-1 chloride It was selected primarily to circumvent the steric hindrance introduced by the ABL T315I “gatekeeper” SIN-1 chloride 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 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.
    Discussion The structures presented here were solved at high resolution and show in detail how DDR1 achieves high affinity for imatinib and ponatinib, respectively. Both type II inhibitors bind in their more potent extended conformations to the inactive DFG-out conformation of the kinase domain. Differences to ABL are observed primarily in the P-loop, where DDR1 adopts the active conformation common to the KIT–imatinib complex (KIT, mast/stem cell growth factor receptor) [43]. As a result, residues in the DDR1 P-loop that confer drug resistance when introduced in ABL are solvent exposed and tolerated. DDR1 also assembles a cage-like structure around the inhibitor pocket by tethering the activation segment to the αD helix. This alternative loop arrangement stabilizes the DFG-out conformation of DDR1 and establishes a distinct packing from other structures. This conformation is exploited by the first DDR1-selective type II inhibitors that carry variant head and linker moieties that restrict interaction with the gatekeeper residue [35], [44]. Interestingly, the ether bridge of DDR1-IN-1 is also found in the MET (hepatocyte growth factor receptor) inhibitor LY2801653, which has entered clinical trials for advanced cancer and inhibits DDR1 with IC50 and EC50 values of less than 1nM [45]. Imatinib-mediated inhibition of breakpoint cluster region-ABL has shown remarkable safety and efficacy against CML [26]. Perhaps more significantly, the recognition of imatinib activity against other kinases, notably KIT and PDGFR (platelet-derived growth factor receptor), has led to its effective use in other oncology indications [46], [47] and ongoing clinical trials in fibrosis [48]. Collagen-induced activation of the RTKs DDR1 and DDR2 is similarly observed in fibrotic diseases and neoplastic tissue suggesting that DDR inhibition may be a beneficial off-target effect. Furthermore, ponatinib and dasatinib show potent activity against mutant DDR2 in models of squamous cell lung cancer [20] and indeed dasatinib has entered clinical trials for this indication [49]. DDR kinases share a conserved threonine gatekeeper residue with ABL and are therefore likely to remain susceptible to drug resistance mutations at this site. The aminopyrimidine head group of imatinib is hydrogen bonded to the gatekeeper Thr701 in DDR1 analogous to its interaction with the gatekeeper Thr315 in ABL [27]. In CML, mutation of the gatekeeper Thr315 to Ile confers drug resistance [50], suggesting that an analogous mutation in DDR1 and DDR2 would also confer resistance to imatinib.