Targeting transthyretin in Alzheimer's disease: Drug discovery of small-molecule chaperones as disease-modifying drug candidates for Alzheimer's disease

Ellen Y Cotrina,Luis Miguel Santos,Josep Rivas,Daniel Blasi,José Pedro Leite,Márcia A Liz,Maria Antònia Busquets,Antoni Planas,Rafel Prohens,Ana Gimeno,Jesús Jiménez-Barbero,Luis Gales,Jordi Llop,Jordi Quintana,Isabel Cardoso,Gemma Arsequell

doi:10.1016/j.ejmech.2021.113847

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.

Highlights

Alzheimer’s disease (AD) is a progressive neurodegenerative disease and is the leading cause of dementia
Using our high throughput screening (HTS) proprietary ternary assay,24 we have evaluated these 53 small-molecule compounds and have obtained a subset of small molecule chaperones (SMCs), among them our lead compound IDIF, one clinical phase compound, and three approved drugs for other diseases, that could enter clinical trials for AD as repurposed drugs
From (1:0) to (1:2); and (B) binary [A [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42] + TTR] at a ratio (2:1) and ternary interactions [A [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42] + (TTR+small-molecule chaperones (SMCs))] at a ratio (2:1:2)

Summary

Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative disease and is the leading cause of dementia. One of the most difficult challenges in AD research is to find a disease modifying therapy (DMT), this is, a therapy with an agent that produces an enduring (permanent) change in the course of AD. AD has no currently approved DMTs. The five drugs available in the market are involved in only improving symptoms and are highly patient dependent, and no putative disease modifying drugs or new symptomatic treatments have achieved regulatory approval since 2003.3There are 121 agents in the current AD treatment pipeline, 36 of them in phase III, 65 in phase II and 27 in phase I clinical trials. 97 agents (80%) are in disease modification trials.

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Conclusion