6EOY

Transthyretin in complex with 4-(1,3-Benzothiazol-2-yl)-2-methylaniline

Summary for 6EOY

• Entry DOI: 10.2210/pdb6eoy/pdb
• Descriptor: Transthyretin, 4-(1,3-benzothiazol-2-yl)-2-methyl-aniline (3 entities in total)
• Functional Keywords: transthyretin, amyloid, ttr amyloid inhibitor, transport protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 25692.85

Authors

Leite, J.P.,Gales, L. (deposition date: 2017-10-10, release date: 2021-10-06, Last modification date: 2024-01-17)

Primary citation

Cotrina, E.Y.,Santos, L.M.,Rivas, J.,Blasi, D.,Leite, J.P.,Liz, M.A.,Busquets, M.A.,Planas, A.,Prohens, R.,Gimeno, A.,Jimenez-Barbero, J.,Gales, L.,Llop, J.,Quintana, J.,Cardoso, I.,Arsequell, G.
Targeting transthyretin in Alzheimer's disease: Drug discovery of small-molecule chaperones as disease-modifying drug candidates for Alzheimer's disease.
Eur.J.Med.Chem., 226:113847-113847, 2021

PubMed Abstract: Transthyretin (TTR) has a well-established role in neuroprotection in Alzheimer's Disease (AD). We have setup a drug discovery program of small-molecule compounds that act as chaperones enhancing TTR/Amyloid-beta peptide (Aβ) interactions. A combination of computational drug repurposing approaches and in vitro biological assays have resulted in a set of molecules which were then screened with our in-house validated high-throughput screening ternary test. A prioritized list of chaperones was obtained and corroborated with ITC studies. Small-molecule chaperones have been discovered, among them our lead compound Iododiflunisal (IDIF), a molecule in the discovery phase; one investigational drug (luteolin); and 3 marketed drugs (sulindac, olsalazine and flufenamic), which could be directly repurposed or repositioned for clinical use. Not all TTR tetramer stabilizers behave as chaperones in vitro. These chemically diverse chaperones will be used for validating TTR as a target in vivo, and to select one repurposed drug as a candidate to enter clinical trials as AD disease-modifying drug.

PubMed: 34555615
DOI: 10.1016/j.ejmech.2021.113847

Experimental method

X-RAY DIFFRACTION (1.38 Å)