Addex Pharmaceuticals has developed drug discovery tools that can be used to screen its small molecule compound library for positive allosteric modulators (protein regulators) of TrkB, a neuroprotective receptor. We have screened several independent chemical series of a type of chemical compounds, called TrkB PAMs, which can become optimized (improved) to become potential Parkinson's disease (PD) therapies. This project aims to optimize chemicals to generate one or more compounds that will confirm the TrkB PAM approach as a potential new treatment strategy for PD.
Brain-derived neurotrophic factor (BDNF), a molecule that helps cells grow, and is associated with symptoms of PD. BDNF also binds to the TrkB receptor. Allosteric modulation is a new approach for delivering therapies to affect BDNF by targeting the TrkB receptor. We aim to demonstrate that TrkB PAMs are effective for PD.
Using our knowledge of this new chemical series, we will create new TrkB PAM compounds and test them in cells expressing TrkB receptors. We will also check several other characteristics of the compounds (the ability to bind to the receptor, chemical stability and if it can be delivered to the brain) to identify the best candidates to test in pre-clinical models of PD.
Impact on Diagnosis/Treatment of Parkinson's disease:
TrkB PAMs have the potential to offer a new approach for the treatment of PD. Due to the complex activation process of TrkB, the traditional approach (full block of the BDNF binding site) is not possible. An alternative method requires targeting a different binding site. Allosteric modulators are a new class of small molecules with drug-like properties. Here, we will test their safety and efficacy.
Next Steps for Development:
The next steps for the project will focus on two major objectives as follows:
- Confirming the potential of TrkB PAM to treat PD with at least one lead compound successfully identified during this funding period, with improved potency and appropriate drug profile;
- Further optimization of this compound to generate a drug ready for clinical studies.