Marta Duran Martinez
OC20 – Marta Duran Martinez
Departamento de Química Orgánica y Química Inorgánica, Universidad de Alcalá (IRYCIS), RICORS-2040, Instituto de Investigación Química “Andrés M. Del Río” (IQAR), INNOREN-CM, 28805-Alcalá de Henares, Madrid, Spain
| New PROTAC approaches targeting the pseudokinase ILK |
| Marta Durán Martínez,1 José Luis Aceña,1 Laura Calleros,2 Sergio de Frutos García,2 Diego Rodríguez Puyol,3 Javier García Marín1 1 Departamento de Química Orgánica y Química Inorgánica, Universidad de Alcalá (IRYCIS), RICORS-2040, Instituto de Investigación Química “Andrés M. Del Río” (IQAR), INNOREN-CM, 28805-Alcalá de Henares, Madrid, Spain. 2 Departamento de Biología de Sistemas, RICORS 2040, Fundación Renal Iñigo Álvarez de Toledo, INNOREN-CM, Universidad de Alcalá (IRYCIS), (IQAR), 28805-Alcalá de Henares, Madrid, Spain. 3 Departamento de Medicina, Universidad de Alcalá, Servicio de Nefrología del Hospital Príncipe de Asturias, Instituto Ramon y Cajal de Investigación Sanitaria, RICORS 2040, Fundación Renal Iñigo Álvarez de Toledo, INNOREN-CM, Alcalá de Henares, 28871 Madrid, Spain |
| Abstract Pseudokinases represent an underexplored class of proteins with key regulatory roles in cell signaling. Notably, no proteolysis-targeting chimeras (PROTACs) have been reported to date for pseudokinases, highlighting a significant gap in the field of targeted protein degradation. Integrin-linked kinase (ILK), a well-characterized pseudokinase, is implicated in multiple pathological processes, including cancer and chronic kidney disease, and provides an attractive model to address this challenge and explore its potential as therapeutic target. In this work, we describe the design and synthesis of a novel PROTAC aimed at inducing the selective degradation of ILK via the ubiquitin–proteasome system. The proposed molecule combines an ILK-binding ligand with an E3 ligase recruiter through a rationally designed linker to promote proximity-driven ubiquitination and subsequent degradation of the target protein.  Figure 1. ILK PROTAC design |
| References [1] de Frutos, S., Luengo, A., Garcia-Jerez, A., Hatem-Vaquero, M., Griera. M., O’Valle, F., Rodriguez-Puyol, D., Calleros, L. Biochim. Biophys. Acta, 2019, 1865(6):1284-1297.Author 1, A.; Author 2, B. Title of the chapter. In Book Title, 2nd ed.; Editor 1, A., Editor 2, B., Eds.; Publisher: Publisher Location, Country, 2007; Volume 3, pp. 154–196. [2] Garcia-Marín, J., Griera, M., Matamoros-Recio, A., de Frutos, S., Rodriguez-Puyol, M., Alajarin, R., Rodriguez-Puyol, D, Vaquero, J.J. ACS. Med. Chem. Lett., 2021, 12(11):1656-1662. |