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PMID: 19736552 Published · ppublish English Journal Article Review

An overview of small-molecule inhibitors of VEGFR signaling.

Nature reviews. Clinical oncology ·Vol. 6 ·No. 10 ·2009-10-00 ·Pages 569-79

Ivy SP, Wick JY, Kaufman BM

Abstract

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.

MeSH Terms
Angiogenesis Inhibitors/adverse effects,pharmacokinetics,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,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
Chemicals
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
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Ivy S Percy
Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA. ivyp@ctep.nci.nih.gov
Wick Jeannette Y
Kaufman Bennett M
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Article Info
Journal
Nature reviews. Clinical oncology
Abbr.
Nat Rev Clin Oncol
ISSN
1759-4782
DOI
10.1038/nrclinonc.2009.130
Email
ivyp@ctep.nci.nih.gov
Published
2009-10-00
Epub
2009-00-08
Pages
569-79
Language
English
Region
England
NLM ID
101500077
Subset
IM
External Links
PubMed source DOI: 10.1038/nrclinonc.2009.130 View journal details
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