7OY6

Crystal structure of human DYRK1A in complex with ARN25068

Summary for 7OY6

• Entry DOI: 10.2210/pdb7oy6/pdb
• Descriptor: Dual specificity tyrosine-phosphorylation-regulated kinase 1A, ~{N}4-(3-cyclopropyl-1~{H}-pyrazol-5-yl)-~{N}2-(phenylmethyl)thieno[3,2-d]pyrimidine-2,4-diamine (3 entities in total)
• Functional Keywords: inhibitor, complex, gsk-3b, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 42225.71

Authors

Tripathi, S.K.,Balboni, B.,Demuro, S.,DiMartino, R.,Ortega, J.,Girotto, S.,Cavalli, A. (deposition date: 2021-06-23, release date: 2022-03-02, Last modification date: 2024-10-23)

Primary citation

Demuro, S.,Sauvey, C.,Tripathi, S.K.,Di Martino, R.M.C.,Shi, D.,Ortega, J.A.,Russo, D.,Balboni, B.,Giabbai, B.,Storici, P.,Girotto, S.,Abagyan, R.,Cavalli, A.
ARN25068, a versatile starting point towards triple GSK-3 beta /FYN/DYRK1A inhibitors to tackle tau-related neurological disorders.
Eur.J.Med.Chem., 229:114054-114054, 2022

PubMed 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.

PubMed: 34959172
DOI: 10.1016/j.ejmech.2021.114054

Experimental method

X-RAY DIFFRACTION (2.38 Å)