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. More recently, drugs have been developed that combine molecular targets within a single type of cancer or patient. Medicinal chemistry faces the challenge of optimizing target potency and selectivity when a single agent is designed, and faces even more challenging design requirements for a single molecule with multiple targets. Since combination chemotherapy 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-target 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.
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. More recently, drugs have been developed that combine molecular targets within a single type of cancer or patient. Medicinal chemistry faces the challenge of optimizing target potency and selectivity when a single agent is designed, and faces even more challenging design requirements for a single molecule with multiple targets. Since combination chemotherapy 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-target 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.
Authors: Channing J Paller; Penelope A Bradbury; S Percy Ivy; Lesley Seymour; Patricia M LoRusso; Laurence Baker; Larry Rubinstein; Erich Huang; Deborah Collyar; Susan Groshen; Steven Reeves; Lee M Ellis; Daniel J Sargent; Gary L Rosner; Michael L LeBlanc; Mark J Ratain Journal: Clin Cancer Res Date: 2014-08-15 Impact factor: 12.531
Authors: Anna Burford; Suzanne E Little; Alexa Jury; Sergey Popov; Ross Laxton; Lawrence Doey; Safa Al-Sarraj; Juliane M Jürgensmeier; Chris Jones Journal: PLoS One Date: 2013-08-21 Impact factor: 3.240
Authors: Christopher Merritt; Lisseth E Silva; Angela L Tanner; Kenneth Stuart; Michael P Pollastri Journal: Chem Rev Date: 2014-10-07 Impact factor: 60.622