2. Academic Validation
  3. A Polypharmacology-Driven Approach to Alzheimer's Disease and Tauopathies: Rational Design, Synthesis and Characterization of Amino-Pyrazole-Based Multikinase (GSK-3β/FYN-α/DYRK1A) Inhibitors

A Polypharmacology-Driven Approach to Alzheimer's Disease and Tauopathies: Rational Design, Synthesis and Characterization of Amino-Pyrazole-Based Multikinase (GSK-3β/FYN-α/DYRK1A) Inhibitors

  • J Med Chem. 2026 May 14;69(9):9991-10018. doi: 10.1021/acs.jmedchem.5c01810.
Stefania Demuro 1 2,  Debora Russo 3,  Ilaria Penna 3,  Siranuysh Grabska 4 5,  Hovakim Grabski 4 5,  Andrea Dalle Vedove 6 7,  Aurora Valeri 8,  Conall Sauvey 4,  Giuliana Ottonello 9,  Maria Summa 10,  Sine Mandrup Bertozzi 9,  Jose Ortega 1,  Rosalia Bertorelli 10,  Paola Storici 7,  Stefania Girotto 1,  Gabriele Cruciani 11,  Rita M C Di Martino 1,  Ruben Abagyan 4,  Andrea Cavalli 1 2
Affiliations

Affiliations

  • 1 Computational and Chemical Biology, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy.
  • 2 Department of Pharmacy and Biotechnology, University of Bologna, via Belmeloro 6, 40126 Bologna, Italy.
  • 3 D3 PharmaChemistry, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy.
  • 4 Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, La Jolla, San Diego, California 92093, United States.
  • 5 L.A. Orbeli Institute of Physiology, National Academy of Sciences, Yerevan 0028, Armenia.
  • 6 AREA Science Park, Padriciano 99, 34149 Trieste, Italy.
  • 7 Protein Targets for Drug Discovery Lab, Elettra Sincrotrone Trieste S.C.p.A., SS 14 - km 163,5 in AREA Science Park, 34149 Trieste, Italy.
  • 8 Molecular Horizon srl, via Montelino 20, 06084 Bettona, Italy.
  • 9 Analytical Chemistry Facility, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy.
  • 10 Translational Pharmacology Facility, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy.
  • 11 Department of Chemistry, Biology and Biotechnology, University of Perugia, via dell'Elce di Sotto 8, 06123 Perugia, Italy.
PMID: 42054438 DOI: 10.1021/acs.jmedchem.5c01810
Abstract

Accumulation of microtubule-associated protein tau is a neurotoxic hallmark in Alzheimer's disease (AD) and related tauopathies. To date, no small molecule disease-modifying therapy exists, underscoring an urgent unmet need. In this context, the multitarget-directed ligand (MTDL) approach offers a viable polypharmacological option for modulating key pathways/targets involved in tau pathology. Leveraging the interconnected roles of GSK-3β, Fyn, and DYRK1A in tau hyperphosphorylation, we conducted a computational and X-ray crystallography-driven SAR exploration around our previously disclosed GSK-3β/Fyn/DYRK1A inhibitor ARN25068 (1). Modification of the thieno[3,2-d]pyrimidine central core of 1 led to the discovery of quite well-balanced GSK-3β/Fyn/DYRK1A triple-targeting analogs (27, 28 (ARN25699) and 31 (ARN26646)). Among these, 28 displayed a favorable ADME profile, acceptable pharmacokinetic properties, and efficacy in an in vitro tau phosphorylation assay, outperforming three single-target inhibitors tested individually or in combination. These compounds represent promising MTDL leads poised to advance therapeutic innovation in AD and related tauopathies.

Figures
Products