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
  • 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.

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