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
  • 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: [email protected].
  • 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: [email protected].
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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