Medchem and Chemical biology approach
Multi-action compounds for the treatment of multi-functional neurodegenerative diseases.
Alzheimer’s disease is a multifactorial slow and progressive dementing disease that combines two pathophysiological mechanisms: the amyloid pathology and the Tau pathology. The first one results from extraneuronal aggregation of amyloid-beta peptides that derive from cleavages of a large transmembrane precursor named amyloid protein precursor (APP). The second one corresponds to intraneuronal accumulation and aggregation of abnormally modified microtubule-associated tau proteins, to form the so-called neurofibrillary tangles. Disease-modifying small molecules currently in clinical trials only act on either one or the other of these processes or are supposed to cure the symptoms.
Our objective is to develop of disease-modifying compounds to target APP processing and to design multi-effect compounds. The developed compounds will also be evaluated on cellular models of other neurodegenerative diseases.
We showed that chloroquine-derived compounds and lysomotropic agents were able to increase neuroprotective fragments of APP while decreasing the secretion of Aβ peptides. The compounds we developed are able to modulate the APP metabolism, reduce the Tau pathology development in vivo and improve the cognitive deficits in a transgenic mouse model of hippocampal Tau pathology. AZP2006, the lead compound, developed by AlzProtect, a start-up company co-founded by P Melnyk, is ending clinical phase I [1,2].
Our efforts were dedicated to
1) Characterize the structure activity relationships of these compounds ,
2) Use these structure-activity relationships rules to add new activities on these compounds (acetylcholinesterase inhibition, ..) and obtain multi-target compounds [4,5],
3) Develop a ligand-based approach and design new families of compounds [6-8],
4) elucidate the mechanism of action of these compounds.
1. Melnyk P, Sergeant N, Buée L, Delacourte A, WO 2006 051489.
2. Barrier M, Buée L, Burlet S, Delacourte A, Estrella C, Melnyk P, Sergeant N, Verwaerde P, WO2014/102339.
3. Melnyk P et al, ACS Chem Neurosci, 2015, 6(4), 559-69.
4. Serageant N et al, Neurobiology of Disease, 2019, SO969-9961, 30327-9
5. Melnyk P, LeFur N, Gay M, Sergeant N, Buée L, Ep 8
6. Gay M et al, Bioorg Med Chem, 2018, 26, 2151-64
7. Gay M et al, Eur J Med Chem 2018, 159, 104-125.
8. Carato P, Descamps F, El Bakali J, Evrard C, Gay M, Melnyk P, Renault N, Sergeant N, Vingtdeux V, EP 8.