Southall, Noel (NCATS)
Zanlungo, Silvana (Pontifical Catholic University of Chile)
Alvarez, Alejandra (Pontifical Catholic University of Chile)
Ferrer-Alegre, Marc (NCATS)
Dulcey Gracia, Andreas (NCATS)
Hu, Xin (NCATS)
Talley, Daniel (NCATS)
Dextras, Christopher (NCATS)
This technology includes a variety of structures that can effectively target the c-Abl myristate binding pocket with increased potency and brain permeability. C-Abl is a ubiquitous non-receptor tyrosine kinase involved in signal transduction. In addition to its classic function in leukemia pathogenesis, c-Abl kinase is also thought to play a role in neuronal health, whereby deregulation of c-Abl could be related to early neuronal dysfunction and cytoskeletal alterations. Mounting evidence points to the role of the Abl tyrosine kinase family as an important player in Alzheimer’s Disease, and thus a potential therapeutic target to delay and ameliorate neurodegeneration. Modelling and cell-based structure-activity relationships were used to guide the optimization and diversification of ligands that are capable of crossing the blood brain barrier (BBB), and bind to the myristate pocket on the c-Abl tyrosine kinase.
Treatment for Alzheimer’s Disease and other neurodegenerative diseases.
- Molecules display favorable physical properties for BBB penetration, a prerequisite for neurodegenerative diseases
- Discovery includes the allosteric mode of inhibition of c-Abl, which renders our molecules exquisitely selective against other kinases, a problem commonly encountered in kinase inhibition programs