Cyclic isoDGR and RGD Peptidomimetics Containing Bifunctional Diketopiperazine Scaffolds are Integrin Antagonists

Abstract

The cyclo[DKP-isoDGR] peptidomimetics 2-5, containing bifunctional diketopiperazine (DKP) scaffolds that differ in the configuration of the two DKP stereocenters and in the substitution at the DKP nitrogen atoms, were prepared and examined in vitro in competitive binding assays with purified αv β3 and αv β5 integrin receptors. IC50 values ranged from low nanomolar (ligand 3) to submicromolar with αv β3 integrin. The biological activities of ligands cyclo[DKP3-RGD] 1 and cyclo[DKP3-isoDGR] 3, bearing the same bifunctional DKP scaffold and showing similar αV β3 integrin binding values, were compared in terms of their cellular effects in human U373 glioblastoma cells. Compounds 1 and 3 displayed overlapping inhibitory effects on the FAK/Akt integrin activated transduction pathway and on integrin-mediated cell infiltration processes, and qualify therefore, despite the different RGD and isoDGR sequences, as integrin antagonists. Both compounds induced apoptosis in glioma cells after 72 hour treatment.

Synthesis, Characterization, and Biological Evaluation of a Dual‐Action Ligand Targeting αvβ3 Integrin and VEGF Receptors

“…This was further confirmed by the inhibition of the phosphorylation of Akt, a serine/threonine‐specific protein kinase that plays a key role in the regulation of vascular homeostasis and angiogenesis. Unlike angiogenesis, other parameters such as cell viability, cell proliferation, and mRNA levels of α V , β 3 , or β 5 integrin subunits were not affected by the administration of compound 1 …”

Brain infiltration by cancer cells: different roads to the same target?

“…[10,12] Integrin inhibitors with different molecular structures have been studied and are in clinical trials as anti-angiogenic agents or in support of other anti-cancer therapies, therefore integrin antagonists could represent a valuable and near-at-hand tool to inhibit the integrin dependent TGF-β activation and eventually reduce metastatic spread. [13] Lung, breast cancer and melanoma are tumors that display the EMT phenotype, [14,15] and in lung cancer, the expression of markers of this transition has been associated with prognosis. [16][17][18] This link between EMT and malignancy is further supported by the finding that, in other cancer types, EMT markers are overexpressed in 40% of tissue samples and are associated with vascular invasion and advanced clinical stage.…”

The Importance of Detail: How Differences in Ligand Structures Determine Distinct Functional Responses in Integrin αvβ3

“…Such DKP‐based ligands proved to be low‐nanomolar α v β 3 ligands, with affinities comparable to Cilengitide . In particular, cyclo [DKP3‐RGD] and cyclo [DKP3‐isoDGR] (respectively compounds 2 and 3 in Figure ) show IC 50 values of 4.5 and 9 n m for α v β 3 , respectively . In human U373 glioblastoma cells, cyclo [DKP3‐RGD] and cyclo [DKP3‐isoDGR] showed inhibitory effects on the FAK/Akt integrin‐activated transduction pathways as well as on the integrin‐mediated cell infiltration process.…”

“…In human U373 glioblastoma cells, cyclo [DKP3‐RGD] and cyclo [DKP3‐isoDGR] showed inhibitory effects on the FAK/Akt integrin‐activated transduction pathways as well as on the integrin‐mediated cell infiltration process. Additionally, they induced apoptosis in glioma cells after treatment for 72 h …”