Increasing αvβ3 Selectivity of the Anti-Angiogenic Drug Cilengitide by N-Methylation
Angewandte Chemie, 2011, DOI: 10.1002/anie.201102971, Volume 50, Issue 40, pages 9496–9500 published on 26.09.2011
The drug Cilengitide, c(RGDf(NMe)V), is a cyclic RGD pentapeptide (R=arginine, D=aspartic acid, G=glycine) currently in clinical phase III for the treatment of brain tumors and in phase II for other cancer types. The antitumoral properties of this peptide are based on its antagonistic activity for pro-angiogenic integrins, such as alpha-v-beta3, alpha-v-beta5, or alpha5 beta1. However, the specific roles of these integrin subtypes in angiogenesis and cancer are not yet clear and fully understood. In this work, we present di-N-methylated analogues of the stem peptide c(RGDfV) which retain an alpha-v-beta3- binding activity in the nanomolar range but have lost most of the activity for integrins alpha-vbeta5 and/or alpha5 beta1. Highly active and selective peptides for alpha-v-bets3 are important tools to study the specific role of this integrin in angiogenesis and cancer.