Shah Kamal, Gopal Krishan, Kumar Shivendra, Saha Sunam
Institute of Pharmaceutical Research, GLA University, Mathura, UP, 281406, India.
Anticancer Agents Med Chem. 2025;25(7):460-467. doi: 10.2174/0118715206351185241209053053.
AXL, a receptor tyrosine kinase, has emerged as a critical player in tumorigenesis, metastasis, and resistance to conventional therapies. Its aberrant activation drives cell proliferation, survival, and angiogenesis, making it an attractive target for cancer treatment. In recent years, significant progress has been made in the development of AXL inhibitors. Chemical approaches have led to the discovery of small molecules that selectively bind to and inhibit AXL, disrupting its downstream signaling pathways. These inhibitors exhibit diverse structural features, including ATP-competitive and allosteric binding modes, offering potential advantages in terms of selectivity and potency. In addition to chemical approaches, biological strategies have also been explored to target AXL. These include the use of monoclonal antibodies, which can neutralize AXL ligands or induce receptor internalization and degradation. Furthermore, gene therapy techniques have been investigated to downregulate AXL expression or disrupt its signaling pathways. Despite these advancements, challenges remain in the development of AXL inhibitors. Selectivity is a critical concern, as AXL shares homology with other receptor tyrosine kinases. Drug resistance is another obstacle, as cancer cells can develop mechanisms to evade AXL inhibition. Furthermore, to address these challenges, combination therapies are being explored, such as combining AXL inhibitors with other targeted agents or conventional treatments. In conclusion, developing AXL inhibitors represents a promising avenue for improving cancer treatment outcomes. Continued research efforts are essential to overcome the existing challenges and translate these compounds into effective clinical therapies.
AXL是一种受体酪氨酸激酶，已成为肿瘤发生、转移及对传统疗法耐药过程中的关键因子。其异常激活会驱动细胞增殖、存活及血管生成，使其成为癌症治疗的一个有吸引力的靶点。近年来，AXL抑制剂的研发取得了重大进展。化学方法已促成了能选择性结合并抑制AXL的小分子的发现，从而破坏其下游信号通路。这些抑制剂呈现出多样的结构特征，包括ATP竞争性和别构结合模式，在选择性和效力方面具有潜在优势。除了化学方法，还探索了针对AXL的生物学策略。这些策略包括使用单克隆抗体，其可中和AXL配体或诱导受体内化及降解。此外，还研究了基因治疗技术以下调AXL表达或破坏其信号通路。尽管取得了这些进展，但AXL抑制剂的研发仍面临挑战。选择性是一个关键问题，因为AXL与其他受体酪氨酸激酶存在同源性。耐药性是另一个障碍，因为癌细胞可形成逃避AXL抑制的机制。此外，为应对这些挑战，正在探索联合疗法，如将AXL抑制剂与其他靶向药物或传统治疗相结合。总之，开发AXL抑制剂是改善癌症治疗效果的一条有前景的途径。持续的研究工作对于克服现有挑战并将这些化合物转化为有效的临床疗法至关重要。
