Introduction Cancer which is responsible

Introduction Cancer, which is responsible for a million deaths each year, is universally feared, and approximately 50% of newly diagnosed cases can be cured [1]. The existing cancer treatments, including surgery, chemotherapy, radiotherapy or a combination of them, are quickly losing efficacy. The low cure rate, serious side effects, and continuous rising morbidity and mortality rates necessitate the need for novel therapy strategies. The TAM family (Tyro3, Axl, Mer) has been reported to regulate different biological processes, including intracellular signaling, cytoskeletal functions, and gene expression. The TAM family shares a unique KWIAIES conserved sequence, and the transcription products of TAM genes show homology in the tyrosine kinase domain. TAMs are widely expressed in the heart, liver, hippocampus, and cerebellum of the brain, as well as in platelets, monocytes, and endothelial cells. Moreover, increasing lines of evidence have highlighted the carcinogenicity of TAMs to promote the proliferation, apoptosis, survival, and metastasis of neoplasms [2]. Axl (ARK, TYRO7, and UFO) receptor tyrosine kinase, an important member of the TAM family, has been shown to be aberrantly overexpressed in a variety of malignancies [3] (Table 1). Overexpression or activation of AXL is strongly linked to cell proliferation, survival, migration, and invasion by activating the oncogenic signaling pathways, including PI3K/Akt and/or MAPK/Erk pathways [[4], [5], [6]]. In addition, AXL can serve as a protector of blood vessels, promoter of cell differentiation in the erythrocyte lineage, sweeper of apoptotic cells, and regulator of pro-inflammatory cytokines [7]. AXL is also associated with hematopoiesis, platelet aggregation, and angiogenesis [8]. Mer has been implicated in a variety of malignancies [[9], [10], [11]], the oncogenic potential of MerTK has been proved [12]. The Mer is also related to the down-regulation of the immune system and phagocytosis after apoptosis [13]. Tyro3 is known to be restrictedly expressed in tissues and is associated with myelination in the Melatonin [14] and metastasis in cancers [15]. Recently, small molecule tyrosine kinase inhibitors targeting Axl have been demonstrated to be significantly effective. This review article updates the understanding of Axl inhibitors and presents a new approach for their potential application.
Axl receptor tyrosine kinase
Axl inhibitors In view of the importance of Axl in promoting cell proliferation, chemotherapy resistance, invasion, and metastasis, investigators have been designing and developing Axl inhibitors for malignant tumors. The inhibitors described below are ATP-competitive inhibitors. The inhibitors contain an adenine-mimicking heterocyclic moiety that binds to the hinge region of the ATP site. Some of them bind to the active conformation of Axl (aspartate–phenylalanine–glycine (DFG) motif oriented toward the active site or DFG-in, type I inhibitors), others adopt an extended conformation by interactions with DFG residues of the activation loop to enter an allosteric region (only accessible in the inactive DFG-out conformation of the kinase, type II inhibitors) [109]. Below is a summary of some representative Axl inhibitors (Fig. 4).
Current & future developments The overall prevalence and mortality of cancer worldwide are on the rise. Many traditional therapies are ineffective due to the pathological and etiological complexity of cancer. Moreover, some treatments like chemotherapy have severe side effects. The demand for effective and safe anti-cancer strategies is ever increasing. The important role of Axl in cancer occurrence and development has been elucidated. The overexpression of Axl has been proven to be one of the critical causes of the chemoresistance of various cancers. The pharma industry and the medical community are expressing increased interest in Axl inhibitors. However, results indicating that Axl acts as the main driver of the cancer are rarely reported, so Axl inhibitors tend to be chosen as combination partners. As described in this review, single-target Axl inhibitors, dual Axl/Met inhibitors, and multi-target Axl inhibitors have been developed. Of these, multi-target Axl inhibitors have been demonstrated to have the strongest ability to defeat advanced cancers and reduce drug resistance (Table 2). For instance, LDC1267 and bosutinib are used to treat advanced cancers, and SGI-7079 and sunitinib are applied for carcinomas that are resistant to other RTK inhibitors. Therefore, multi-target Axl inhibitors are more promising for future applications. In addition, a better understanding of Axl could lead to more effective anticancer strategies.