9FR7

Crystal structure of human GSK3B in complex with ARN25507

This is a non-PDB format compatible entry.

Summary for 9FR7

• Entry DOI: 10.2210/pdb9fr7/pdb
• Descriptor: Glycogen synthase kinase-3 beta, ~{N}4-(5-cyclopropyl-1~{H}-pyrazol-3-yl)-~{N}2-(phenylmethyl)furo[3,2-d]pyrimidine-2,4-diamine (3 entities in total)
• Functional Keywords: kinase inhibitors, multitarget compounds, drug discovery, central nervous system, tauopathies, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 99264.36

Authors

Dalle Vedove, A.,Demuro, S.,Di Martino, R.M.C.,Balboni, B.,Tripathi, S.K.,Storici, P.,Girotto, S.,Cavalli, A. (deposition date: 2024-06-18, release date: 2026-01-14, Last modification date: 2026-07-29)

Primary citation

Demuro, S.,Russo, D.,Penna, I.,Grabska, S.,Grabski, H.,Dalle Vedove, A.,Valeri, A.,Sauvey, C.,Ottonello, G.,Summa, M.,Bertozzi, S.M.,Ortega, J.,Bertorelli, R.,Storici, P.,Girotto, S.,Cruciani, G.,Di Martino, R.M.C.,Abagyan, R.,Cavalli, A.
A Polypharmacology-Driven Approach to Alzheimer's Disease and Tauopathies: Rational Design, Synthesis and Characterization of Amino-Pyrazole-Based Multikinase (GSK-3 beta /FYN-alpha /DYRK1A) Inhibitors.
J.Med.Chem., 69:9991-10018, 2026

PubMed 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 (). Modification of the thieno[3,2-]pyrimidine central core of led to the discovery of quite well-balanced GSK-3β/FYN/DYRK1A triple-targeting analogs (, (ARN25699) and (ARN26646)). Among these, 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.

PubMed: 42054438
DOI: 10.1021/acs.jmedchem.5c01810

Experimental method

X-RAY DIFFRACTION (2.3 Å)