9HV3

Crystal structure of human GSK3b in complex with ARN25657

This is a non-PDB format compatible entry.

Summary for 9HV3

• Entry DOI: 10.2210/pdb9hv3/pdb
• Related: 9HUK 9HUL
• Descriptor: Glycogen synthase kinase-3 beta, 2-oxidanylidene-~{N}-[3-(4-phenylpiperazin-1-yl)propyl]-6-pyridin-3-yl-3~{H}-benzimidazole-1-carboxamide (2 entities in total)
• Functional Keywords: kinase inhibitors, multitarget compounds, drug discovery, bipolar disorder, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 99484.67

Authors

Dalle Vedove, A.,Di Martino, R.M.C.,Storici, P.,Girotto, S.,Cavalli, A.,Bottegoni, G. (deposition date: 2024-12-24, release date: 2025-07-23)

Primary citation

Di Martino, R.M.C.,Russo, D.,Penna, I.,Demuro, S.,Dalle Vedove, A.,Spagnuolo, R.,Ottonello, G.,Bertozzi, S.M.,Summa, M.,Desantis, J.,Valeri, A.,Pruccoli, L.,Tripathi, S.K.,Tarozzi, A.,Storici, P.,Girotto, S.,Bertorelli, R.,Armirotti, A.,Cruciani, G.,Bandiera, T.,Cavalli, A.,Bottegoni, G.
Rational optimization of D3R/GSK-3 beta dual target-directed ligands as potential treatment for bipolar disorder: Design, synthesis, X-ray crystallography, molecular dynamics simulations, in vitro ADME, and in vivo pharmacokinetic studies.
Eur.J.Med.Chem., 297:117899-117899, 2025

PubMed Abstract: Bipolar disorder is a complex neuropsychiatric condition with a significant unmet medical need, as current treatments lack disease-modifying properties and multimodal therapeutic effects. To overcome the limitations of single-target drugs, we designed dual-target ligands that combine partial agonism at the dopamine D3 receptor (D3R) with inhibition of glycogen synthase kinase-3β (GSK-3β). We previously identified ARN24161 (1) as a promising prototype, demonstrating partial agonism at D3R (EC = 10.1 nM, % Eff. = 26.3) and GSK-3β inhibition (IC = 561 nM). However, its drug-like properties remained suboptimal. To optimize this compound, we initiated a multidisciplinary refinement campaign, leveraging computational modeling and crystallographic data to fine-tune the balance between D3R and GSK-3β activity, reduce P-glycoprotein (P-gp) affinity, and improve the pharmacokinetic profile. This effort led to the identification of ARN25297 (5), a moderately balanced dual-target ligand that exhibits partial agonism at D3R (EC = 13.1 nM, % Eff. = 17.1) and potent GSK-3β inhibition (IC = 47.0 nM). Notably, ARN25657 (16) emerged as the most well-balanced candidate, demonstrating enhanced D3R partial agonism (EC = 15.2 nM, % Eff. = 37.7) alongside strong GSK-3β inhibition (IC = 19.3 nM). Compound 16 also exhibited the lowest P-gp inhibition and significant improvements in in vitro ADME properties compared to prototype 1, while maintaining a balanced dual target profile. Although the PK profile of 16 remained comparable to that of prototype 1, these findings lay the groundwork for further lead optimization and structural refinement, driving future in vivo proof-of-concept toward innovative therapeutic strategies for bipolar disorder and related neuropsychiatric conditions.

PubMed: 40639291
DOI: 10.1016/j.ejmech.2025.117899

Experimental method

X-RAY DIFFRACTION (2.9 Å)