Development of vascular endothelial growth factor receptor (VEGFR) kinase inhibitors as anti-angiogenic agents in cancer therapy.
Among the known angiogenic growth factors and cytokines implicated in the modulation of normal and pathological angiogenesis, the VEGF family (VEGF-A, VEGF-B, VEGF-C, VEGF-D) and their corresponding receptor tyrosine kinases [VEGFR-1 (Flt-1), VEGFR-2 (Flk-1, KDR), and VEGFR-3 (Flt-4)] play a paramount and indispensable role in regulating the multiple facets of the angiogenic and lymphangiogenic processes, as well as the induction of vascular permeability and inflammation. The receptor VEGFR-2/KDR is the principal one through which VEGFs exert their mitogenic, chemotactic, and vascular permeabilizing effects on the host vasculature. Increased expression of VEGFs by tumor cells and VEGFR-2/KDR and VEGFR-1/Flt-1 by the tumor-associated vasculature are a hallmark of a variety of human and rodent tumors in vivo and correlates with tumor growth rate, micro-vessel density/proliferation, tumor metastatic potential, and poorer patient prognosis in a variety of malignancies. Approaches to disrupting the VEGF/VEGFR signaling cascade range from biological agents (soluble receptors, anti-VEGF and anti-VEGFR-2 antibodies, and VEGF transcription inhibitors) to small molecule ATP competitive VEGFR inhibitors. Examples from this latter class that are currently in clinical development include compounds from distinct chemical classes such as: indolin-2-ones, anilinoquinazolines, anilinophthalazines, isothiazoles, indolo- and indenocarbazoles. The structure activity relationships, biochemical and pharmacological profile of optimized representatives from each of these classes constitute the subject matter of this review.
Underiner
T L
TL
Departments of Chemistry and Oncolgy, Cephalon, Inc, West Chester, PA, USA. tunderin@cephalon.com
Ruggeri
B
B
Gingrich
D E
DE
D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002986:Clinical Trials as Topic; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D020533:Angiogenesis Inhibitors; D004791:Enzyme Inhibitors; D040262:Receptors, Vascular Endothelial Growth Factor