Moreover showed reduction in fibroblast growth factor induce

Moreover, showed 73% reduction in fibroblast growth factor–induced neovascularization in a mouse corneal micropocket assay at a dose of 100mg/kg and 50% reduction at 50mg/kg. Both results were highly statistically significant (P<0.001, ). In this model the anti-angiogenic effect of was again comparable to that of the positive control Sunitinib (78% reduction at 80mg/kg). In summary, a series of potent dual inhibitors of Axl kinase and VEGF-R2 have been developed around a diaminotriazole core. Off-target INSR activity and cytotoxicity was reduced to acceptable levels, although selectivity against closely-related TAM family RTK Mer was not achieved. Several members of this series were suitable for oral delivery and one of these, , showed activity comparable to the clinically approved tyrosine kinase inhibitor Sunitinib in mouse tumor xenograft models and the corneal micropocket angiogenesis model. Interestingly, anti-Axl Cyanine 5-dCTP have recently shown only moderate efficacy (40% inhibition) in an A549 tumor cell mouse xenograft model. Inhibition of both Axl and VEGF-R2 might therefore be more effective in preventing angiogenesis and tumor growth than targeting either receptor alone. In fact we observed (and it has been subsequently reported) that Sunitinib shows potent 9nM in vitro inhibition of Axl, as well as potent VEGF-R2, Flt-3 and Kit activity. The potential therapeutic benefits of using dual Axl/VEGF-R2 inhibitors, especially in patients who have relapsed after VEGF-R2 targeted therapy have been highlighted in a recent Perspective on Axl inhibitors in cancer. Acknowledgement
Introduction Lung cancer is the most common cancer worldwide. About 85% of lung cancer is non-small cell lung cancer (NSCLC), which is less aggressive and relatively insensitive to anti-cancer agents, while small cell lung cancer (SCLC) accounts for 10% of lung cancer and has higher growth rate and is more easily metastasized than NSCLC (Ettinger et al., 2013). In case of NSCLC, platinum- or taxol-based chemotherapy is the standard first line treatment (Chen et al., 2014). Since intrinsic or the acquired resistance to these agents limits their therapeutic effects, targeted therapy or combined regimens has been applied as an alternative approach to overcome these obstacles (Forde and Ettinger, 2013). However, the overall survival rate of NSCLC patients still remains fairly low. Among 58 receptor tyrosine kinases (RTKs) in the human genome, which classified into 20 subfamilies, TAM family is a small subfamily with only three members which are Tyro3 (also referred to Brt, Dtk, Rse, Sky or Tif), Axl (also referred to Ark, Tyro7, or Ufo) and Mer (also referred to Eyk, Nyk, or Tyro12) (Graham et al., 1994, Lai et al., 1994, O'Bryan et al., 1991). The structural features of these TAM RTKs are so similar, which are the extracellular domain with two immunoglobin-like and two fibronectin type III domains, single transmembrane domain and cytosolic kinase domain (Heiring et al., 2004, Sasaki et al., 2006). In addition, they share several ligands such as growth arrest-specific 6 (Gas 6), protein S, tubby, and tulip to transduce extracellular signals for cell survival, proliferation, invasion, migration (Goruppi et al., 1996, Shiozawa et al., 2010). Gas6 has been reported to be able to engage and activate all three TAM RTKs (Nagata et al., 1996). Axl is first identified as a novel RTK in 1988 and cloned from chronic myelogenous leukemia patients in 1991 (O'Bryan et al., 1991). Upregulation of Axl expression and its activation has been observed in diverse types of cancers including acute leukemia (Rochlitz et al., 1999), breast (Berclaz et al., 2001), colorectal (Martinelli et al., 2015), ovarian (Rankin et al., 2010) and prostate (Shiozawa et al., 2010) to result in cell survival, proliferation and inhibition of apoptosis. Interestingly, in NSCLC, head and neck cancer, chronic myelogenous leukemia and gastrointestinal stromal tumors, the overexpression and/or activation of Axl found to be a mechanism to get the acquired resistance against epidermal growth factor receptor (EGFR) inhibitors, gefitinib (Bae et al., 2015) or erlotinib (Giles et al., 2013), and tyrosine kinase inhibitor, imatinib (Dufies et al., 2011), respectively. MicroRNAs or monoclonal antibodies which specifically target Axl have been reported to inhibit the proliferation of NSCLC cells in vitro as well as in vivo (using tumor xenografts) (Gazdar, 2010, Wang et al., 2014). Therefore, Axl seems be potent enough as a therapeutic target to treat cancer and overcome chemoresistance.