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

Transthyretin (TTR) has a well-established role in neuroprotection, evidenced in Alzheimer’s Disease (AD). By targeting TTR we have setup a drug discovery program of small-molecule compounds that act as chaperones, enhancing TTR/ amyloid-β peptide (Aβ) interactions. In a first stage, we carried out two computational drug repurposing approaches. In a second stage, the computationally selected compounds were assessed for their ability to bind and stabilize the TTR tetramer, using thyroxine displacement tests, and by assessing the level of monomers, respectively. In a third stage, the selected 53 best performing molecules were run through our in-house validated high-throughput screening ternary test. By targeting TTR in our AD drug discovery program, small-molecule chaperones (SMCs) have been discovered, providing the basis for a novel target for Alzheimer’s disease (AD) based on their enhancement of the TTR/Abeta interaction. Among the SMCs, we have found our lead small-molecule 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. Importantly, we found that not all TTR tetramer stabilizers are good SMCs in vitro, emphasizing the importance of our discovery program. A small set of these SMCs will be prioritized to enter preclinical safety studies, to validate TTR as a target in vivo, and to select one repurposed drug as a candidate to enter clinical trials for AD. We envisage that this new target will feed the currently exhausted pipeline of drugs in phase I for AD with the goal of increasing AD disease-modifying therapies.