Summary of - Positive allosteric modulators of Trk-receptors for the treatment of Alzheimer’s disease

Pontus Forsell, Cristina Parrado Fernández, Boel Nilsson, Johan Sandin, Gunnar Nordvall, M?rta Segerdahl

For questions or more information mail: [email protected]

Link to original and referred to article: https://www.mdpi.com/2889430

The article discusses the development and therapeutic potential of Trk (tropomyosin receptor kinase) receptor modulators for treating neurodegenerative diseases, with a focus on Alzheimer's disease (AD). Neurotrophins (NTs) like NGF (nerve growth factor), BDNF (brain-derived neurotrophic factor), and NT-3 have shown promise in preclinical and clinical studies for their ability to support neuronal survival, growth, and repair. Various methods have been explored to deliver these neurotrophins into the brain, including viral vectors and direct injections, but challenges such as side effects, including pain, have been problematic for their further development. Recent research has focused on small-molecule positive allosteric modulators (PAMs) of Trk receptors, which offer a more targeted and potentially safer approach than direct administration of neurotrophins. PAMs bind to Trk receptors at sites distinct from the endogenous ligand binding site, allowing them to modulate receptor activity selectively without triggering widespread receptor activation, thus minimizing side effects like increased pain sensation. These modulators can fine-tune Trk receptor signaling to enhance neurotrophic support in diseases like AD, where neurotrophin levels are often diminished. Several small molecules, including natural products and synthetic compounds, have been identified as potential Trk modulators. Notable examples include 7,8-dihydroxyflavone, BNN27, and LM22B-10. However, the reproducibility of these compounds' effects and their ability to reliably activate Trk receptors have been questioned. Some compounds have shown promise in preclinical models, but translating these findings into clinical success remains a challenge. Two novel PAMs, E2511 and ACD856, have shown significant promise. E2511, developed by Eisai, selectively modulates TrkA receptors and has demonstrated neurotrophic effects without inducing pain in preclinical models. It has progressed to phase I clinical trials, where it was found to be safe and well-tolerated. It has also shown potential disease-modifying effects in preclinical models of AD. ACD856, developed by AlzeCure Pharma, is a pan-Trk modulator that affects multiple Trk receptors. It has shown efficacy in enhancing memory performance, reversing memory impairment, and exhibiting antidepressant effects in preclinical studies. Furthermore, ACD856 has been shown to display neuroprotective and neuroregenerative effects in preclinical models, indicating potential disease modifying effecs. It has also progressed to clinical trials, where it demonstrated good brain penetration, central target engagement, and a favorable safety profile. ACD856's ability to improve cognitive function and neuronal plasticity suggests it could complement existing AD treatments like cholinesterase inhibitors and anti-amyloid antibodies. The compound is now being prepared for phase II clinical trials in patients. The ongoing development of Trk receptor modulators, particularly PAMs, represents a promising new avenue for treating AD and other neurodegenerative conditions. These compounds could address aspects of neurodegeneration and cognitive dysfunction that are not fully managed by current therapies, offering hope for more effective treatment strategies in the future.