Chemical probes based on proximity-inducing pharmacology

   

Javi graduated in Pharmacy from the University of Granada in 2009. After 3 years working outside academia, he joined the University of Barcelona, where he gained his MSc and PhD in 2013 and 2017, respectively, under the supervision of Prof. Diego Muñoz-Torrero. His research dealt with the discovery of multi-target directed ligands for the treatment of Alzheimer’s disease.

He joined the group of Dr. daCosta at the University of Ottawa for both predoctoral and postdoctoral stays in 2017 and 2018, working on electrophysiology studies of nicotinic acetylcholine receptors.

In 2018, he returned to the University of Barcelona for a year and aimed at the identification of ligands for TET2, a project led by Dr. Héctor G. Palmer and Dr. Xavier Barril.

Later, he was granted two postdoctoral fellowships by Ramon Areces Foundation and Marie Skłodowska-Curie Actions to work in the Prof. David Spring group at the University of Cambridge (2019-2023) and the Prof. Alessio Ciulli group at the University of Dundee (2023). During this time, he worked in the fields of antibody-drug conjugates (ADCs) and targeted protein degradation (TPD).

Finally, in November 2023, he started his own group, aiming at the discovery of chemical tools for the mechanistic study of distinct autophagy processes as well as deubiquitinating enzymes.

Our research focuses on proximity-inducing pharmacology approaches, an emerging field that is driving a next generation of chemotherapeutics. This strategy has the potential to overcome major limitations of classical drug interventions, such as a limited proteome targetability. It is based on small molecules that hijack a protein effector of the cellular machinery to modulate the activity of a protein of interest (POI), thereby evoking a certain biological process. Mechanistically, proximity-inducer compounds contain two different pharmacophoric motifs, being able to bring two proteins together, which allows the chemical modification of the POI by the effector protein. The most significant example for this approach comprises the engagement of the ubiquitin-proteasome system by means of the recruitment of an E3 ubiquitin ligase as a protein effector, triggering the transference of a ubiquitin tag to the POI, which will subsequently be degraded by the proteasome.

Proximity inducers can be greatly useful not only as therapeutics but also as biological tools for research purposes. These tools, also known as chemical probes, are extremely useful in fundamental biomedical research, enabling a confident investigation of protein biology and disease.

In this context, the group has 2 main lines of research:

- Expanding the toolbox for deubiquitinating enzymes (DUBs). We aim at the discovery of proximity inducers that can be used as chemical probes for DUBs.

- Unveiling the mechanisms of autophagy. We pursue the dissection of autophagy-related signalling pathways through proximity-inducer chemical probes.

Vincent Sul (Bachelor Thesis Research from Maatricht University)

Aya El Allam Kanice (undergraduate student)

Red-light modulated ortho-chloro azobenzene photoswitch for peptide stapling via aromatic substitution

M. Kapun, F.J. Pérez-Areales, N. Ashman, P.J.E. Rowing, T. Schober, E. Fowler, L.S. Itzhaki, D.R. Spring

RSC Chem. Biol. 2024, 5, 49

 

Hybrid androgen receptor inhibitors outperform enzalutamide and EPI-001 in in vitro models of prostate cancer drug resistance

R.C. Bizga Nicolescu, Z. Maylin, F.J. Pérez-Areales, J. Iegre, H. Pandha, M. Asim, D.R. Spring

ChemMedChem 2023, 18, e202200548

Selected “Very Important Paper” and Front Cover (ChemMedChem 2023, 18, e202200703).

 

Ancestral acetylcholine receptor β-subunit forms homopentamers that prime before opening spontaneously

C.J. Tessier, R.M. Sturgeon, J.R. Emlaw, G.D. McCluskey, F.J. Pérez-Areales, C.J.B. daCosta

eLife 2022, 11, e76504

 

Unveiling the multitarget anti-Alzheimer drug discovery landscape: a bibliometric analysis

A. Sampietro, F.J. Pérez-Areales, P. Martínez, E.M. Arce, C. Galdeano, D. Muñoz-Torrero

Pharmaceuticals 2022, 15, 545

 

Centrally active multitarget anti-Alzheimer agents derived from the antioxidant lead CR-6

F.J. Pérez-Areales, M. Garrido, E. Aso, M. Bartolini, A. De Simone, A. Espargaró, T. Ginex, R. Sabaté, B. Pérez, V. Andrisano, D. Puigoriol-Illamola, M. Pallàs, F.J. Luque, M.I. Loza, J.M. Brea, I. Ferrer, F. Ciruela, A. Messeguer, D. Muñoz-Torrero

J. Med. Chem. 2020, 63, 9360

 

A novel class of multitarget anti-Alzheimer benzohomoadamantane‒chlorotacrine hybrids modulating cholinesterases and glutamate NMDA receptors

F.J. Pérez-Areales, A.L. Turcu, M. Barniol-Xicota, C. Pont, D. Pivetta, A. Espargaró, M. Bartolini, A. De Simone, V. Andrisano, B. Pérez, R. Sabate, F.X. Sureda, S. Vázquez, D. Muñoz-Torrero

Eur. J. Med. Chem. 2019, 180, 613

 

Back to the future: rational maps for exploring acetylcholine receptor space and time

C.J. Tessier, J.R. Emlaw, Z.Q. Cao, F.J. Pérez-Areales, J.-P.J. Salameh, J.E. Prinston, M.S. McNulty, C.J.B. DaCosta

BBA Proteins and Proteomics 2017, 1865, 1522

 

Ancestral reconstruction approach to acetylcholine receptor structure and function

J.E. Prinston, J.R. Emlaw, M.F. Dextraze, C.J.G. Tessier, F.J. Pérez-Areales, M.S. McNulty, C.J.B. DaCosta

Structure 2017, 25, 1295

 

Design, synthesis, and multitarget biological profiling of a second generation of anti-Alzheimer rhein–huprine hybrids

F.J. Pérez-Areales, N. Betari, A. Viayna, C. Pont, A. Espargaró, M. Bartolini, A. De Simone, J.F.R. de Alvarenga, B. Pérez, R. Sabaté, R.M. Lamuela-Raventós, V. Andrisano, F.J. Luque, D. Muñoz-Torrero

Fut. Med. Chem. 2017, 9, 965.

 

Synthesis and biological evaluation of N-cyanoalkyl-, N-aminoalkyl-, and N-guanidinoalkyl-substituted 4-aminoquinoline derivatives as potent, selective, brain permeable antitrypanosomal agents

I. Sola, A. Artigas, M.C. Taylor, F.J. Pérez-Areales, E. Viayna, M.V. Clos, B. Pérez, C.W. Wright, J.M. Kelly, D. Muñoz-Torrero

Bioorg. Med. Chem. 2016, 24, 5162.

 

Shogaol-huprine hybrids: Dual antioxidant and anticholinesterase agents with beta-amyloid and tau anti-aggregating properties

F.J. Pérez-Areales, O. Di Pietro, A. Espargaró, A. Vallverdú-Queralt, C. Galdeano, I.M. Ragusa, E. Viayna, C. Guillou, M.V. Clos, B. Pérez, R. Sabaté, R.M. Lamuela-Raventós, F.J. Luque, D. Muñoz-Torrero

Bioorg. Med. Chem. 2014, 22, 5298

 

Tetrahydrobenzo[h][1,6]naphthyridine-6-chlorotacrine hybrids as a new family of anti-Alzheimer agents targeting beta-amyloid, tau, and cholinesterase pathologies

O. Di Pietro, F.J. Pérez-Areales, J. Juárez-Jiménez, A. Espargaró, M.V. Clos, B. Pérez, R. Lavilla, R. Sabaté, F.J. Luque, D. Muñoz-Torrero

Eur. J. Med. Chem. 2014, 84, 107

We are always pleased to recruit talented and motivated scientists. We consider applications from scientists at all the different stages of their career, from undergraduate students to postdocs. If you are interested in joining our research group, please feel free to contact us at fjperezareales@ub.edu.

 

Address:

Laboratory of Medicinal Chemistry

Faculty of Pharmacy and Food Sciences

University of Barcelona

Av. Joan XXIII, 27-31

08028 - Barcelona (Spain)

(link: Facultat de Farmàcia)