An overview of small-molecule inhibitors of VEGFR signaling

Nat Rev Clin Oncol. 2009 Oct;6(10):569-79. doi: 10.1038/nrclinonc.2009.130. Epub 2009 Sep 8.


VEGFR inhibitors are in broad use for the treatment of metastatic renal-cell carcinoma, gastrointestinal stromal tumors and hepatocellular carcinoma and in development in a number of other oncology indications, including colorectal cancer, non-small-cell lung cancer, pancreatic cancer, thyroid malignancies, ovarian cancer, breast cancer and sarcomas. This Review outlines the structure-activity relationships of the 44 VEGFR inhibitors currently in development. An overview of the pharmacokinetic profile of each molecule and its stage in development is provided. Phase III clinical trials being conducted for licensing of these agents for specific indications and phase III developmental efficacy trials are described in detailed tables that include the disease studied, trial design including combination therapy, study end points, and projected or final accrual. The relative frequency of on-target and off-target adverse events observed in 3,060 patients is described for a subset of agents in development in clinical trials sponsored by the National Cancer Institute. No interagent comparisons were undertaken and no data from pharmaceutical pharmacovigilance databases were used. The on-target effects seem to be mechanistically based and predicted by VEGFR inhibition. Small-molecule inhibitors of angiogenesis are active in a wide variety of malignancies and fill a unique niche for cancer therapeutics.

Publication types

  • Review

MeSH terms

  • Angiogenesis Inhibitors / adverse effects
  • Angiogenesis Inhibitors / pharmacokinetics*
  • Angiogenesis Inhibitors / therapeutic use*
  • Animals
  • Antineoplastic Agents / therapeutic use
  • Benzenesulfonates / therapeutic use
  • Cadherins / metabolism
  • Clinical Trials, Phase III as Topic
  • Extracellular Matrix Proteins / metabolism
  • Humans
  • Indoles / therapeutic use
  • Integrins / metabolism
  • Intercellular Signaling Peptides and Proteins / metabolism
  • National Cancer Institute (U.S.)
  • Neoplasms / classification
  • Neoplasms / drug therapy*
  • Niacinamide / analogs & derivatives
  • Peptide Hydrolases / metabolism
  • Phenylurea Compounds
  • Protein Kinase Inhibitors / therapeutic use
  • Pyridines / therapeutic use
  • Pyrroles / therapeutic use
  • Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors*
  • Signal Transduction / drug effects*
  • Sorafenib
  • Structure-Activity Relationship
  • Sunitinib
  • Transcription Factors / metabolism
  • United States


  • Angiogenesis Inhibitors
  • Antineoplastic Agents
  • Benzenesulfonates
  • Cadherins
  • Extracellular Matrix Proteins
  • Indoles
  • Integrins
  • Intercellular Signaling Peptides and Proteins
  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • Pyridines
  • Pyrroles
  • Transcription Factors
  • Niacinamide
  • Sorafenib
  • Receptors, Vascular Endothelial Growth Factor
  • Peptide Hydrolases
  • Sunitinib