Modification of Integrin Ligand Receptors May Lead to Personalized Cancer Diagnosis and Treatment

Chemical modification of the guanidine group was used to modify the receptor subtype specificity for the integrin ligand cilengitide, which is an advance that may lead to patient-specific diagnoses and subsequent targeted treatment of tumor cells.

Cilengitide is a molecule designed and synthesized at the Technical University Munich (Germany) in conjunction with Merck KGaA (Darmstadt, Germany). It is based on the cyclic peptide cyclo(-RGDfV-), which is selective for alpha-v integrins, which are important in angiogenesis and other aspects of tumor biology.


Integrins are transmembrane receptors that mediate the attachment between a cell and the tissues that surround it, such as other cells or the extracellular matrix (ECM). Integrin molecules do not adhere to their appropriate ligands until cells are activated by chemotactic agents or other stimuli. Only then do the integrins undergo the conformational change necessary to confer high binding affinity for the endothelial adhesion molecules

Due to its unique role as a hydrogen-bond donor and its positive charge, the guanidine group is an important pharmacophoric group and often used in synthetic ligands. The chemical modification of the guanidine group is often considered to destroy its function.

In a study published in the December 9, 2015, online edition of the journal Angewandte Chemie investigators at the Technical University of Munich showed that the N-methylation, N-alkylation, or N-acylation of the guanidine group could be used to modify the receptor subtype specificity for the integrin ligand cilengitide.

Using the alphavbeta6/alpha5beta1-biselective ligand and the alphavbeta6-specific ligand as examples, the investigators demonstrated that the binding affinities of the ligands could be fine-tuned by this method to enhance the selectivity for alphavbeta6. Furthermore, they described a new strategy for the functionalization of integrin ligands through the introduction of N-alkylguanidine and N-acylguanidine groups. In this fashion, they were able to simultaneously identify a hitherto unknown anchoring point and enhance the subtype selectivity of the ligand.

"If we knew which integrin subtypes are active in the specific cancer of a given patient, we could attack these using appropriate active agents," said first author Tobias Kapp, a doctoral candidate in chemistry at the Technical University of Munich. "For this we need compounds that attach to a single integrin as specifically as possible."

"We now know the form of the lock and we know how to make the matching key," said senior author Dr. Horst Kessler, professor chemistry at the Technical University of Munich. "This opens the door to a personalized medicine with which we can take patient-specific action against tumor cells."

Related Links:
Technical University Munich
Merck KGaA