Recent advances in the development of EGFR/Src, Src/Abl, EGFR/VEGFR2, EGFR/c-Met, STAT-3/c-Src, VGERF/FAK and EGFR/HER dual-targeted kinase inhibitors

INTRODUCTION: Although several therapies have been applied for cancer treatment and mutations, drug resistance remains a significant impediment to the efficient use of single-therapy. Multi-targeting therapies are designed to combat these problems by using two different methodologies: either combining medications to create a synergistic effect on different targets or designing and producing multiple-targeting medicines that efficiently block the many carcinogenic pathways synergistically. AREAS COVERED: From the literature, the information on classical and high-impact dual tyrosine kinase inhibitors derived based on their design concepts, chemical classes, and therapeutic effects is summarized. Various chemical scaffolds have dual-targeting activities to overcome drug resistance driven by genetic mutations and their structure-activity relationship studies are shown. ADVANTAGES, DISADVANTAGES, AND FUTURE PERSPECTIVES: The latest investigations have shown that dual-acting drugs can simultaneously suppress critical cancer cell features, and provide the synergistic effect through inhibition of two or more proteins, improving safety profile, and enhancing pharmacokinetic properties of compounds. Recent clinical investigations emphasize the synergistic potential of combining Src and EGFR inhibitors. However, novel dual inhibitors may have a resistance problem due to unknown mutations, and heterodimerization. Despite these disadvantages, the coherent results on dual kinase inhibitors indicate that there are still chances to obtain promising therapeutic approaches.