Increasing alpha-v-beta-3 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

Angewandte Chemie, online article

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-beta-3, alpha-v-beta-5, or alpha-5-beta-1. 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-beta-3- binding activity in the nanomolar range but have lost most of the activity for integrins alpha-v-beta-5 and/or alpha-5-beta-1. Highly active and selective peptides for avb3 are important tools to study the specific role of this integrin in angiogenesis and cancer. Integrins are heterodimeric receptors that govern cell–cell and cell–extracellular matrix (ECM) interactions, and play crucial roles in a plethora of cellular functions.The fact that many integrins are involved in pathological processes, such as tumor angiogenesis, has stimulated their study as therapeutic targets. A number of integrin receptors recognize and bind the tripeptide sequence RGD, which is a prominent celladhesion motif present in ECM proteins. Mimicking this tripeptide sequence with RGD-peptides or peptidomimetics is hence a promising approach to target integrins involved in angiogenesis and to develop anti-cancer agents.It is known that alpha-v-beta-3 and alpha-v-beta-5 are involved in two different angiogenic pathways. Whereas angiogenesis induced by basic fibroblast growth factor (bFGF) or tumor necrosis factor-a depends on alpha-v-beta-3, angiogenesis triggered by vascular endothelial growth factor (VEGF) or transforming.

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