Therapeutic potential of novel selective-spectrum kinase inhibitors in oncology

Background: In. recent years, several small molecularly-targeted kinase inhibitors have been tested in the clinic for the treatment of cancer. One category of these agents provides selective targeting of a single kinase pathway. is most often required for optimal benefit, the potential benefit to combining targets in one agent is of considerable interest in drug development. Objectives: A comparison was undertaken between selectively targeted tyrosine kinase inhibitors (TKI) with a single target, multiple-targeted TKI within a single pathway and TKI with an extended spectrum of targets from more than a single pathway, to determine whether multiple or extended-TKI have greater clinical utility than selective TKI. Methods: TKI that target the epidermal growth factor receptor (EGFR) and the vascular receptors (vascular endothelial growth factor [VEGF], platelet-derived growth factor [PDGF]) were reviewed, since the number of agents available allows comparisons to be reached. Preclinical, pharmacological, pharmacodynamic and clinical data were considered. Results: In the vascular therapeutic area, multiple-targeted TKI definitely have greater efficacy than selectively targeted agents, and there is also a trend in the EGFR area. Extended-spectrum TKI are only now in the clinic, but Phase I and early Phase II results are promising. Conclusions: This article discusses characteristics that candidate kinase inhibitors must possess to be acceptable for clinical use and the current state of development of several of these agents, including single-targeted kinase inhibitors, multiple-targeted single-spectrum kinase inhibitors, and extended-spectrum selective kinase inhibitors. Finally, it provides a description of challenges for the future development for this class of novel therapeutics. It appears that the greater number of targets produces a greater clinical benefit. The logistical challenges to the use of a combination of selective agents have not yet been overcome.