2. Academic Validation
  3. ARN25068, a versatile starting point towards triple GSK-3β/FYN/DYRK1A inhibitors to tackle tau-related neurological disorders

ARN25068, a versatile starting point towards triple GSK-3β/FYN/DYRK1A inhibitors to tackle tau-related neurological disorders

  • Eur J Med Chem. 2022 Feb 5;229:114054. doi: 10.1016/j.ejmech.2021.114054.
Stefania Demuro 1,  Conall Sauvey 2,  Shailesh K Tripathi 3,  Rita M C Di Martino 3,  Da Shi 2,  Jose A Ortega 3,  Debora Russo 4,  Beatrice Balboni 1,  Barbara Giabbai 5,  Paola Storici 5,  Stefania Girotto 3,  Ruben Abagyan 6,  Andrea Cavalli 7
Affiliations

Affiliations

  • 1 Computational and Chemical Biology, Istituto Italiano di Tecnologia, Via Morego 30, 16163, Genoa, Italy; Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy.
  • 2 Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, 92093, United States.
  • 3 Computational and Chemical Biology, Istituto Italiano di Tecnologia, Via Morego 30, 16163, Genoa, Italy.
  • 4 D3 PharmaChemistry, Istituto Italiano di Tecnologia, Via Morego, 30, 16163, Genoa, Italy.
  • 5 Protein Facility, Elettra Sincrotrone Trieste S.C.p.A., SS 14 - Km 163, 5 in AREA Science Park, 34149, Trieste, Italy.
  • 6 Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, 92093, United States. Electronic address: ruben@ucsd.edu.
  • 7 Computational and Chemical Biology, Istituto Italiano di Tecnologia, Via Morego 30, 16163, Genoa, Italy; Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy. Electronic address: andrea.cavalli@iit.it.
PMID: 34959172 DOI: 10.1016/j.ejmech.2021.114054
Abstract

The human kinome plays a crucial role in several pathways. Its dysregulation has been linked to diverse central nervous system (CNS)-related disorders with a drastic impact on the aging population. Among them, tauopathies, such as Alzheimer's Disease (AD) and Frontotemporal Lobar degeneration (FTLD-tau), are neurodegenerative disorders pathologically defined by the presence of hyperphosphorylated tau-positive intracellular inclusions known as neurofibrillary tangles (NFTs). Compelling evidence has reported the great potential of the simultaneous modulation of multiple protein kinases (PKs) involved in abnormal tau phosphorylation through a concerted pharmacological approach to achieve a superior therapeutic effect relative to classic "one target, one drug" approaches. Here, we report on the identification and characterization of ARN25068 (4), a low nanomolar and well-balanced dual GSK-3β and Fyn Inhibitor, which also shows inhibitory activity against DYRK1A, an emerging target in AD and tauopathies. Computational and X-Ray studies highlight compound 4's typical H-bonding pattern of ATP-competitive inhibitors at the binding sites of all three PKs. In a tau phosphorylation assay on Tau0N4R-TM-tGFP U2OS cell line, 4 reduces the extent of tau phosphorylation, promoting tau-stabilized microtubule bundles. In conclusion, this compound emerges as a promising prototype for further SAR explorations to develop potent and well-balanced triple GSK-3β/Fyn/DYRK1A inhibitors to tackle tau hyperphosphorylation.

Keywords

Central nervous system; Docking studies; Enzymatic and cell-based assays; Kinase inhibitors; Multitarget compounds; Selectivity; Tau phosphorylation assay; Tauopathies; X-ray studies.

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