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Cilengitide: The First Anti-Angiogenic Small Molecule Drug Candidate. Design, Synthesis and Clinical Evaluation

[ Vol. 10 , Issue. 10 ]


Carlos Mas-Moruno, Florian Rechenmacher and Horst Kessler   Pages 753 - 768 ( 16 )


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 αvβ3, αvβ5 and α5β1. 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 αvβ3 inhibitor (100 to 1000 times increased activity over the linear reference peptides), which in addition exhibited high selectivity against the platelet receptor αIIbβ3. 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.


RGD peptides, integrin antagonists, glioblastoma, N-methylation, conformational restriction, cyclization, Anti-Angiogenic, RGD, ECM, CAM, Angiogenesis, Tumor Vasculature, IMD, NMR, VEGFs, Cilengitide, NSCLC, radio-chemotherapy, ITH, GBM


Institute for Advanced Study, Department Chemie, Technische Universitat Munchen, Lichtenbergstrasse 4, 85747 Garching, Germany.

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