Cancer is a hazardous and lethal disease that affects millions of people worldwide. According to the American Cancer Society, there were 1.9 million new cases of cancer and 60,920 cancer deaths in the United States by the end of 2023 [1]. In addition, the incidence and death rate from cancer in females has exceeded that of males [1], [2]. Common conventional cancer treatments include surgery, chemotherapy, radiation therapy, etc. Surgery is highly effective in the early phase of cancer, but it is pale to treat late-stage or metastatic cancer. Radiation therapy does not require surgery and has a pleasing therapeutic effect on early-stage cancer, but it is also accompanied by toxic side effects, and cancer cells outside the radiation area can not be eliminated. Although chemotherapy extends the survival cycle of patients, but numerous drugs are toxic to normal cells, which dramatically reduces the quality of life of patients [3]. Small molecule targeted therapy is a unique form of chemotherapy that targets specific genes or proteins to inhibit the growth and migration of cancer cells [4]. Therefore, it can help alleviate side effects.

Cellular-mesenchymal epithelial transition factor (c-Met), also named hepatocyte growth factor receptor (HGFR), is a special member of the RTK family [5]. It consists of a semaphorin (SEMA) domain, a plexin-semaphorin-integrin (PSI) domain, and four consecutive extracellular immunoglobulin-plexin transcription factor (IPT1-4) domains, a single transmembrane helix (TM), and an intracellular KD. The c-Met receptor can be activated by either its homologous ligand, hepatocyte growth factor (HGF), or its native subtype NK1 [6]. The combination of c-Met and HGF induces the dimerization of c-Met, leading to autophosphorylation of tyrosine residues in the c-Met intracellular region and subsequent activation of downstream signaling pathways. Finally, the signal is transferred to the nuclear transcriptional machinery, regulating many essential cellular processes such as cell proliferation, motility, morphogenesis, and survival (Fig.1) [7]. c-Met is widely expressed in various cells and tissues. Overexpression of c-Met is associated with many cancers and enhances the transformation of normal cells into malignant cells, especially in colorectal cancer, gastric cancer, and lung cancer [8], [9], [10].

c-Met inhibitors are commonly used to treat cancers by blocking the interactions between ligands and receptors, thereby preventing downstream signal activation through targeted inhibition of c-Met or HGF. However, due to the complexity of cancer, manipulating a single target may result in treatment failure [11]. For example, type I c-Met kinase inhibitors are ATP-competitive. The affinity of inhibitors and c-Met becomes weaker owing to the pocket point mutations in the ATP binding pocket of c-Met, which then occurs. Eventually, cancers treated with type I c-Met kinase inhibitors often became resistant [12]. Drug combination for the treatment of cancers has proven to be a successful strategy, but the use of two or more drugs simultaneously remains a challenge in clinical therapy because of the unfamiliar technology, pharmacological properties, and drug-drug interactions [13]. With the progress of related studies, researchers have gradually explained the multiple signaling pathways mediated by c-Met, c-Met/EGFR, c-Met/ALK, c-Met/AXL, c-Met/HDACs, c-Met/COX-2, etc. In recent years, researchers have increasingly focused on developing novel dual-target drugs due to the advantages of drugs with multiple pharmacological activities over drug combination therapy [14]. This has laid a significant foundation for the further development of single-agent dual-target or multi-target inhibitors.