AXL, a receptor tyrosine kinase encoded by the AXL gene, is a member of the TAM (TYRO3, AXL and MER) family and is renowned for phosphorylating tyrosine residues. Located on chromosome 19q13.2, AXL exists as two isoforms due to alternative splicing: a predominant full-length isoform and a shorter variant, which differs by the inclusion or exclusion of exon 10. When fully glycosylated, AXL has an average mass of 140 kDa, reducing to approximately 120 kDa with partial glycosylation [1]. AXL modulates various pathways, notably enhancing EMT, subsequently increasing cell invasiveness, anti-apoptotic resistance, and acquisition of stem-like properties. Although these alterations may hinder cell proliferation, they advantage cancer cells by facilitating tumor growth and resistance to therapy [2]. AXL activation in both cancerous and stromal cells contributes significantly to disease advancement through effects on angiogenesis, fibrosis, immune evasion, and hypoxia.

High expression of AXL has been observed in various types of cancers, including haematological malignancies as well as solid tumors such as breast, lung and melanoma [[3], [4], [5]] [[3], [4], [5]] [[3], [4], [5]]. Research on molecular mechanisms indicates that activation of AXL stimulates signaling pathways including PI3K-AKT, NF-kappaB, RAS-MEK-ERK, JAK-STAT, and SRC/FAK, thereby impacting various cellular processes such as cancer cell migration, invasion, and metastasis [[6], [7], [8], [9]] [[6], [7], [8], [9]] [[6], [7], [8], [9]]. Furthermore, AXL also demonstrates potential in combination therapy with other drugs. For example, studies have shown that inhibiting AXL can prevent or overcome acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in patients with epidermal growth factor receptor-mutant lung cancer. Therefore, AXL represents a promising therapeutic target [10]. Strategies to inhibit AXL expression, including the application of specific antibodies, have shown promise in reducing tumor cell migration and EMT, especially in Triple Negative Breast Cancer (TNBC) models, enhancing anti-tumor immunity as well [11]. In addition to cancer, AXL is also implicated in the pathogenesis of other diseases. As a host receptor, AXL mediates membrane fusion to facilitate the entry of the SARS-CoV-2 virus. Furthermore, the expression of AXL is closely associated with the viral load and disease symptoms in COVID-19 patients. AXL is a potential target for treating SARS-CoV-2, indicating that repurposing kinase inhibitors directed at AXL could offer a timely and effective strategy for developing new therapies against the virus [12,13].

Currently, many AXL-targeted drugs have entered the clinical trial stage, and some drugs have already demonstrated therapeutic effects. For example, BGB324(1) has entered phase II trials, showing high selectivity and efficacy in the treatment of breast cancer and melanoma, and overcoming drug resistance. Another multi-target inhibitor, TP-0903(2), has shown potential in preclinical models of pancreatic cancer, while Cabozantinib(3), also a multi-target inhibitor, has been effective in the treatment of liver cancer [14,15]. However, there are potential issues that need to be considered, such as the off-target effects of AXL inhibitors. Due to the fact that many receptor tyrosine kinases share common ATP binding sites, inhibitors of other RTKs may also affect AXL; for example, SKI-606(4), while designed as a SRC and ABL kinase inhibitor, also inhibits AXL phosphorylation itself. Therefore, the selectivity of drugs is crucial for the safety and efficacy of clinical treatment. Drugs with poor selectivity may affect non-target related signaling pathways, leading to a series of adverse reactions [16]. At the same time, the degree of inhibition of the target protein by the drug may not be sufficient to achieve therapeutic effects, thus affecting the realization of efficacy (Fig. 1A).

Numerous studies are currently focused on overcoming the challenges faced by AXL inhibitors, including enhancing selectivity and minimizing off-target effects. In-depth research on AXL and its inhibitors is crucial for the development of safe, effective, and highly selective new drugs. We have summarized the structure and functions of AXL, discussed its relationship with cancer, and reviewed recent AXL inhibitors. We have conducted a detailed analysis of the structure-activity relationships, target mechanisms, and inhibitory effects of these inhibitors, aiming to provide new insights and directions for future research and development of AXL inhibitors.