Development of Thiazole-based VEGFR-2 Targeted Agents: A Comprehensive Review of Cytotoxic and Anticancer Activities

Abstract

One of the best-proven molecular targets in the treatment of cancer is vascular endothelial growth factor receptor-2 (VEGFR-2). Because it plays an important role in tumor angiogenesis, proliferation, and metastasis. FDA-approved VEGFR-2 inhibitors have proven to have clinical efficacy in managing various malignancies. Anti-cancer activity of approved agents such as sorafenib (IC50 = 1 µM - 10 µM), sunitinib (IC50 = 1 µM - 5 µM), and pazopanib (IC50 = 1 µM - 3 µM) has been demonstrated. However, their therapeutic use can result in off-target toxicities. Moreover, acquired resistance mechanisms have been observed as well. They also have poorly selective means of action. The 1,3,4-thiadiazole scaffold has become an important heterocyclic compound of medicinal chemistry due to its mesoionic character, versatility in structures, and pharmacological attributes. This review presents a systematic study of the earlier developments in the rational design, synthesis, SAR, and cytotoxicity evaluation of thiazole-based VEGFR-2 inhibitors. In this review, the molecular mechanisms of VEGFR-2 inhibitors and their biological activities against a variety of cancer cell lines in terms of their ability to induce apoptosis, modulate cell cycle, anti-metastatic properties, and in silico approaches. The recently added thiazole derivatives display very good VEGFR-2 inhibitory activities with IC50 values ranging from 0.055 to 0.194 µM, potent antiproliferation activities with IC50 values of 1.5-15 µM, good selectivity indices (3-20-fold), and anticancer activities through different mechanisms of action that are more favorable than the established drugs.