A comprehensive review of protein kinase inhibitors for cancer therapy

Abstract

Introduction: Protein kinases are involved in various cellular functions including metabolism, cell cycle regulation, survival, and differentiation. Dysregulation of protein kinases is implicated in various processes of carcinogenesis. The advent of protein kinase inhibitors in cancer therapy has led to a paradigm shift in how we treat cancer. There are several protein kinase inhibitors that have been approved by FDA in the last few decades. Areas Covered: This article provides a review of the clinical benefits and side effect profiles of FDA approved protein kinase inhibitors as of December 2017 for the well-known oncogenic protein kinases. The role of the respective oncogenic protein kinases in carcinogenesis and cancer progression were searched in PubMed and discussed. The relevant and landmark clinical trials mostly phase III trials of protein kinase inhibitors leading up to the FDA approval were PubMed searched and discussed. Expert Commentary: Further understanding of the molecular origin of cancers would help us identify new targets, while clinical trials trying to identify the appropriate sequence of available kinase inhibitor would make better use of current protein kinase inhibitor armamentarium. Also, testing these drugs in the adjuvant setting in patients with high risk of recurrence might offer some clinical benefit. Development of resistance, side effects and cost are major limitations of protein kinase inhibitors, therefore understanding of the molecular mechanisms of resistance and designing protein kinase inhibitors to obviate the resistance would help overcome the resistance. Finally, collaboration between international organizations for cancer research and voluntary and charity organizations might help reduce the cost.

In Search of Outliers. Mining for Protein Kinase Inhibitors Based on Their Anti-Proliferative NCI-60 Cell Lines Profile

“…Similarities between a known PKI from the predictive set and some of the potential PKIs predicted by the developed method can be observed in Figure 1, where the distributions of upper outliers for both sets (18 known PKIs and top 10 potential PKIs) are presented. For example, out of 8 outliers for each of the compounds, 5 cell lines (8,13,15, 47 and 48) can be seen to be common outliers for both afatinib (dark green in Figure 1a) and NSC 693255, also known as tyrphostin AG-1478 (light blue in Figure 1b). Table 5.…”

“…A great number of small molecules have been developed in the last decades to specifically or selectively target protein kinases as antitumor therapies [1,10,11]. Imatinib was the first kinase inhibitor to reach the market in 2001, and soon became the first-line therapy for chronic myelogenous leukemia patients [12,13]. Second generation PKIs (dasatinib, nilotinib, bosutinib) and third-generation PKIs (ponatinib) were rationally designed to target with high specificity the imatinib-resistant forms of Bcr-Abl oncoprotein [12,14].…”

Epigenetic Effects of Enzastaurin – A New Aspect in the Mechanism of Action of an Anticancer Drug From Protein Kinase Inhibitors

“…To date, 37 drugs of this group have been approved for the treatment of various oncological diseases, including non-small cell lung carcinoma, acute lymphoblastic leukemia, chronic myeloid leukemia, breast cancer, etc. [21]. The ability of protein kinase inhibitors to influence gene expression via epigenetic regulation has not been studied yet.…”

ProfKin: A Comprehensive Web Server for Structure-based Kinase Selectivity Profiling

“…Small molecule inhibitors targeting kinases have great therapeutic potentials, which have been continually proved in clinic in recent decade [6]. By June 2020, a total of 61 kinase inhibitors have been approved by United States Food and Drug Administration; meanwhile, a large number of kinase inhibitors are currently in preclinical and clinical development phase [7][8][9]. Despite an unparalleled success already made in drug discovery targeting kinases, it is still highly desirable to develop more potent and selective kinase inhibitors, particularly for unexploited kinases, which can provide useful chemical tools for target validation as well as drug candidates for therapeutic interventions.…”