DYRK1A inhibitors(Dual-specificity tyrosine-phosphorylation regulated kinase 1A inhibitors), FYN inhibitors(Tyrosine-protein kinase FYN inhibitors), GSK-3β inhibitors(Glycogen synthase kinase-3 beta inhibitors)

Therapeutic Areas

Nervous System Diseases

Active Indication

Alzheimer Disease

Inactive Indication-

Originator Organization

Istituto Italiano di Tecnologia

Active Organization

Istituto Italiano di Tecnologia

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC19H18N6S

InChIKeyTVUWQDLBEOZVOU-UHFFFAOYSA-N

CAS Registry2649882-80-2

100 Clinical Results associated with ARN25068

100 Translational Medicine associated with ARN25068

100 Patents (Medical) associated with ARN25068

Literatures (Medical) associated with ARN25068

23 Mar 2023·Journal of Medicinal ChemistryQ1 · MEDICINE

Comparative Efficacy and Selectivity of Pharmacological Inhibitors of DYRK and CLK Protein Kinases

Q1 · MEDICINE

Article

Author: Deau, Emmanuel ; Alfonso, Patricia ; George, Nicolas ; Corrionero, Ana ; Arfwedson, Jonas ; George, Pascal ; Lindberg, Mattias F ; Meijer, Laurent

Dual-specificity, tyrosine phosphorylation-regulated kinases (DYRKs) and cdc2-like kinases (CLKs) play a large variety of cellular functions and are involved in several diseases (cognitive disorders, diabetes, cancers, etc.). There is, thus, growing interest in pharmacological inhibitors as chemical probes and potential drug candidates. This study presents an unbiased evaluation of the kinase inhibitory activity of a library of 56 reported DYRK/CLK inhibitors on the basis of comparative, side-by-side, catalytic activity assays on a panel of 12 recombinant human kinases, enzyme kinetics (residence time and K_d), in-cell inhibition of Thr-212-Tau phosphorylation, and cytotoxicity. The 26 most active inhibitors were modeled in the crystal structure of DYRK1A. The results show a rather large diversity of potencies and selectivities among the reported inhibitors and emphasize the difficulties to avoid "off-targets" in this area of the kinome. The use of a panel of DYRKs/CLKs inhibitors is suggested to analyze the functions of these kinases in cellular processes.

01 Feb 2022·European Journal of Medicinal ChemistryQ1 · MEDICINE

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

Q1 · MEDICINE

Article

Author: Girotto, Stefania ; Russo, Debora ; Giabbai, Barbara ; Tripathi, Shailesh K ; Sauvey, Conall ; Cavalli, Andrea ; Demuro, Stefania ; Shi, Da ; Ortega, Jose A ; Storici, Paola ; Di Martino, Rita M C ; Balboni, Beatrice ; Abagyan, Ruben

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.

100 Deals associated with ARN25068

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Alzheimer Disease	Preclinical	Italy	Istituto Italiano di Tecnologia	01 Feb 2022

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