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.

Stefania Demuro; Debora Russo; Ilaria Penna; Siranuysh Grabska; Hovakim Grabski; Andrea Dalle Vedove; Aurora Valeri; Conall Sauvey; Giuliana Ottonello; Maria Summa; Sine Mandrup Bertozzi; Jose Ortega; Rosalia Bertorelli; Paola Storici; Stefania Girotto; Gabriele Cruciani; Rita M C Di Martino; Ruben Abagyan; Andrea Cavalli

doi:10.1021/acs.jmedchem.5c01810

Key Points

The aim is to develop multikinase inhibitors that target GSK-3β, FYN-α, and DYRK1A for Alzheimer's disease and tauopathies.
Synthesized amino-pyrazole-based multikinase inhibitors targeting GSK-3β, FYN-α, and DYRK1A.
Conducted in vitro assays for tau phosphorylation to assess efficacy.
Evaluated pharmacokinetic properties and ADME (absorption, distribution, metabolism, excretion) profiles.
The multikinase inhibitors showed superior performance in tau phosphorylation assays compared to three single-target inhibitors.
Exhibited favorable ADME profile and acceptable pharmacokinetics.
Promising candidates for further development as multitarget drug leads in Alzheimer's and tauopathies.

Implication

Demonstrates improved efficacy of multikinase inhibitors in Alzheimer's disease, suggesting enhanced treatment options.

Abstract

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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Cite This Study

Demuro et al. (2026) studied this question.

synapsesocial.com/papers/69f5947e71405d493afff472 https://doi.org/10.1021/acs.jmedchem.5c01810

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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.

Key Points

Implication

Abstract

Discussion

Cite This Study

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.

Key Points

Implication

Abstract

Discussion

Cite This Study

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