Small-Molecule Inhibitors of the Receptor Tyrosine Kinases: Promising Tools for Targeted Cancer Therapies

Abstract

Chemotherapeutic and cytotoxic drugs are widely used in the treatment of cancer. In spite of the improvements in the life quality of patients, their effectiveness is compromised by several disadvantages. This represents a demand for developing new effective strategies with focusing on tumor cells and minimum side effects. Targeted cancer therapies and personalized medicine have been defined as a new type of emerging treatments. Small molecule inhibitors (SMIs) are among the most effective drugs for targeted cancer therapy. The growing number of approved SMIs of receptor tyrosine kinases (RTKs) i.e., tyrosine kinase inhibitors (TKIs) in the clinical oncology imply the increasing attention and application of these therapeutic tools. Most of the current approved RTK–TKIs in preclinical and clinical settings are multi-targeted inhibitors with several side effects. Only a few specific/selective RTK–TKIs have been developed for the treatment of cancer patients. Specific/selective RTK–TKIs have shown less deleterious effects compared to multi-targeted inhibitors. This review intends to highlight the importance of specific/selective TKIs for future development with less side effects and more manageable agents. This article provides an overview of: (1) the characteristics and function of RTKs and TKIs; (2) the recent advances in the improvement of specific/selective RTK–TKIs in preclinical or clinical settings; and (3) emerging RTKs for targeted cancer therapies by TKIs.

Functional Analyses of Mutations in Receptor Tyrosine Kinase Genes in Non–Small Cell Lung Cancer: Double-Edged Sword of DDR2

“…Especially, receptor tyrosine kinases (RTK) have been shown not only to act as key regulators of normal cellular processes, but also to play a critical role in the development and progression of many cancers. Indeed, many drugs that target RTKs, such as EGFR, HER2, ALK, ABL, KIT, and PDGFR, have been approved for many cancers (10). Thus, the identification of alterations in RTK genes could provide a ticket for novel molecular-targeted therapy.…”

Mechanisms of tumor cell resistance to the current targeted-therapy agents

“…As previously described, sorafenib (multi-kinase inhibitor) targets vascular endothelial growth factor receptor (VEGFR) 1-2, BRAF, PDGFR, cKIT, and FLT3 [4]. This TKI has shown broad anti-tumoral activity.…”

“…These SMIs are ATP-competitor TKIs and belong to the first generation of selective EGFR-TKIs [4]. These TKIs are used as the front-line targeted therapy for NSCLC patients with EGFR mutations.…”

“…In addition to sever effects of chemotherapy agents, drug resistance develops after treatment regimens [2]. Therefore, development of new modalities such as targeted-based cancer therapy (TBCT) agents is necessary [3][4][5].…”

Total Structural Elucidation of Erlotinib and Gefitinib by Mainly 2D-Rotating Frame Overhauser Effect Spectroscopy (2D ROESY NMR)

“…Gefitinib is the first EGFRtargeting agent registered as an anticancer drug in Japan and Australia.FDA approved Gefitinib and Erlotinib in 2003 and 2005, respectively. These kinase inhibitors have been widely evaluated in cancer clinical trials 5 .…”