Receptor tyrosine kinases as a therapeutic target by natural compounds in cancer treatment

Abstract

Background Receptor tyrosine kinases (RTKs) are single-pass transmembrane proteins that play significant roles in regulating cellular processes, including cell division and growth. Overexpression and mutations of RTKs have been found in clinical manifestations of different forms of cancer. Therefore, RTKs have received considerable interest as a therapeutic biomarker in the treatment of cancer cells. Main body of the abstract Comprehensive data on RTKs, pharmacological and biological properties of natural compounds were systematically searched up to 2021 using relevant keywords from various databases, such as Google Scholar, PubMed, Web of Science, and Scopus. The scientific search by various standard electronic resources and databases unveils the effectiveness of medicinal plants in the treatment of various cancers. In vitro and in vivo studies suggested that bioactive compounds such as flavonoids, phenols, alkaloids, and many others can be used pharmacologically as RTKs inhibitors (RTKI) either by competing with ATP at the ATP binding site of the tyrosine kinase domain or competing for the receptor extracellular domain. Additionally, studies conducted on animal models indicated that inhibition of RTKs catalytic activity by natural compounds is one of the most effective ways to block the activation of RTKs signaling cascades, thereby hampering the proliferation of cancer cells. Furthermore, various pharmacological experiments, transcriptomic, and proteomic data also reported that cancer cells treated with different plants extracts or isolated phytochemicals exhibited better anticancer properties with minimal side effects than synthetic drugs. Clinically, natural compounds have demonstrated significant anti-proliferative effect via induction of cell apoptosis in cancer cell lines. Short conclusion An in-depth knowledge of the mechanism of inhibition and structural characterization of RTKs is important to the design of novel and selective RTKIs. This review focuses on the molecular mechanisms and structures of natural compounds RTKI targeting vascular endothelial growth factor, epidermal growth factor receptor, insulin receptor, and platelet-derived growth factor while also giving future directions to ameliorate the scientific burden of cancer. Graphic abstract

New Indole‐6‐Carboxylic Acid Derivatives as Multi‐Target Antiproliferative Agents: Synthesis, in Silico Studies, and Cytotoxicity Evaluation

“…Comparing the EGFR TK inhibitory activity of the new indole derivatives (3 a-3 f) incorporating thiosemicarbazide moiety to their corresponding compounds incorporating triazole moiety (4 a-4 c) and oxadiazole moiety (5), indicated that the thiosemicarbazide moiety is more advantageous than the triazole and oxadiazole moieties (Figure 2A). Regarding compounds containing thiosemicarbazide linkers (3 a-3 f), introduction of a methoxy group at p-position (compound 3 f) exhibited lower activity than methyl in p-position (compound 3 c) (Figure 2B), while replacement of the bromo group in the p-position (compound 3 e) with another electronegative substituent as the pchloro group or nitro group (compounds 3 d and 3 b) increases the activity (Figure 2C).…”

“…Receptor tyrosine kinases (RTKs) get activated when a growth factor binds to their extracellular domain and induces dimerization of the receptors. [5] RTKs belonging to the epidermal growth factor receptor (EGFR) family are crucial for controlling cell migration, survival, proliferation, and differentiation. On the other hand, the vascular endothelial growth factor receptor (VEGFR), another RTK, is a crucial component of signal transduction pathways involved in angiogenesis and neovascularization.…”

“…Three structurally-related VEGFRs activate downstream effectors in different cells; VEGFR-1 produced in macrophages and monocytes, while VEGFR-2 and VEGFR-3 are found in lymphocytes and endothelial cells of vascular tissues. [5] Both EGFR and VEGFR-2 are commonly overexpressed by tumor cells.…”

“…Receptor tyrosine kinases (RTKs) get activated when a growth factor binds to their extracellular domain and induces dimerization of the receptors [5] . RTKs belonging to the epidermal growth factor receptor (EGFR) family are crucial for controlling cell migration, survival, proliferation, and differentiation.…”

“…On the other hand, the vascular endothelial growth factor receptor (VEGFR), another RTK, is a crucial component of signal transduction pathways involved in angiogenesis and neovascularization. Three structurally‐related VEGFRs activate downstream effectors in different cells; VEGFR‐1 produced in macrophages and monocytes, while VEGFR‐2 and VEGFR‐3 are found in lymphocytes and endothelial cells of vascular tissues [5] . Both EGFR and VEGFR‐2 are commonly overexpressed by tumor cells.…”