Kinase insert domain-containing receptor kinase inhibitors as anti-angiogenic agents.
A variety of data accumulated during the past 10 years indicates that vascular endothelial growth factor-mediated angiogenesis is a key process in the growth of solid tumours. Efficacious and specific modulation of that signalling event through the inhibition of the cognate tyrosine kinase kinase insert domain-containing receptor (Flk-1) has been reported. A variety of small molecule kinase-domain-containing receptor kinase inhibitors, including SU-5416, SU-6668, PTK-787, midostaurin, ZD4190 and ZD6474, have progressed to the clinical testing stage and this has allowed the direct and critical inspection of preclinical and clinical behaviour. The variety of potency, kinase selectivity and pharmacokinetic profiles offered by this group of compounds is providing important guidance for the efficacious use of these agents today and the design of second and third generation compounds for the future.
Hartman
George D
GD
Department of Medicinal Chemistry, Merck Research Laboratories, WP14-2, West Point, PA 19486, USA. george_hartman@merck.com
Fraley
Mark E
ME
Bilodeau
Mark T
MT
D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D016228:Endothelial Growth Factors / Q000502:physiology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D008222:Lymphokines / Q000502:physiology; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*; D042442:Vascular Endothelial Growth Factors
D020533:Angiogenesis Inhibitors; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D040301:Vascular Endothelial Growth Factor Receptor-2