Journal
ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY
Volume 10, Issue 10, Pages 753-768Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/187152010794728639
Keywords
RGD peptides; integrin antagonists; glioblastoma; N-methylation; alpha v beta 3; conformational restriction; cyclization
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Funding
- Merck
- Jerini
- Deutsche Forschungsgemeinschaft
- Alexander von Humboldt Foundation
- Center for Integrated Protein Sciences Munich (CIPSM)
- Institute for Advanced Study (IAS)
- International Graduate School for Science and Engineering (IGGSE)
- Generalitat de Catalunya
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Cilengitide, a cyclic RGD pentapeptide, is currently in clinical phase III for treatment of glioblastomas and in phase II for several other tumors. This drug is the first anti-angiogenic small molecule targeting the integrins alpha v beta 3, alpha v beta 5 and alpha 5 beta 1. It was developed by us in the early 90s by a novel procedure, the spatial screening. This strategy resulted in c(RGDfV), the first superactive alpha v beta 3 inhibitor (100 to 1000 times increased activity over the linear reference peptides), which in addition exhibited high selectivity against the platelet receptor alpha IIb beta 3. This cyclic peptide was later modified by N-methylation of one peptide bond to yield an even greater antagonistic activity in c(RGDf(NMe) V). This peptide was then dubbed Cilengitide and is currently developed as drug by the company Merck-Serono (Germany). This article describes the chemical development of Cilengitide, the biochemical background of its activity and a short review about the present clinical trials. The positive anti-angiogenic effects in cancer treatment can be further increased by combination with classical anti-cancer therapies. Several clinical trials in this direction are under investigation.
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