Tripeptides as Integrin-Linked Kinase Modulating Agents Based on a Protein-Protein Interaction with α-Parvin.

Javier Garcia-Marin,Diego Rodríguez-Puyol,Sergio De Frutos,Juan J Vaquero,Manuel Rodríguez-Puyol,Alejandra Matamoros-Recio,Ramón Alajarín,Mercedes Griera-Merino

doi:10.1021/acsmedchemlett.1c00183

Abstract

Integrin-linked kinase (ILK) has emerged as a controversial pseudokinase protein that plays a crucial role in the signaling process initiated by integrin-mediated signaling. However, ILK also exhibits a scaffolding protein function inside cells, controlling cytoskeletal dynamics, and has been related to non-neoplastic diseases such as chronic kidney disease (CKD). Although this protein always acts as a heterotrimeric complex bound to PINCH and parvin adaptor proteins, the role of parvin proteins is currently not well understood. Using in silico approaches for the design, we have generated and prepared a set of new tripeptides mimicking an α-parvin segment. These derivatives exhibit activity in phenotypic assays in an ILK-dependent manner without altering kinase activity, thus allowing the generation of new chemical probes and drug candidates with interesting ILK-modulating activities.

Highlights

Integrin-linked kinase (ILK) has emerged as a controversial pseudokinase protein that plays a crucial role in the signaling process initiated by integrin-mediated signaling
Discovered in 1996 by Dedhar and co-workers as a integrin-β1 subunit binding protein,[2] ILK has been known to be a kinase for a long time.[2−5] as its crystal structure revealed a pseudoactive kinase catalytic site (PDB ID: 3KMW), this putative activity as a protein kinase has been questioned and become quite controversial.[6−9] studies with this molecule have led to its validation as a promising therapeutic target for cancer.[3,10,11]
Several studies have demonstrated that ILK acts as a tight heterotrimeric complex in vivo with the two adaptor proteins PINCH and parvin.[7,9,12]

Summary

Author Contributions

Conducted experiments: J.G.-M., A.M.-R., and M.G. Performed data analysis: J.G.-M., M.G.R.A., S.F., D.P., M.P. Funding acquisition and supervision: J.V., D.P. The manuscript was written by J.G.-M. with the contributions of all authors. All authors have given approval to the final version of the manuscript. Funding Spanish Ministerio de Economiá y Competitividad (CTQ2017-85263-R MINECO/FEDER); Instituto de Salud Carlos III and FEDER funds (RD16/0009/0015, RD16/0009/ 0018, PI17/01513, PI17/00625); Comunidad de Madrid (NOVELREN, B2017/BMD-3751, S2017/BMD- 3751). Notes The authors declare the following competing financial interest(s): J.G.-M., M.G.S.de F., R.A., J.V., M.P., and D.P. are coinventors on a patent application filed by the University of Alcala describing the use of tripeptides to modulate ILKmediated actin polymerization (P202030776)

■ ACKNOWLEDGMENTS

Findings

■ REFERENCES