Kinase targets in CNS drug discovery.
Originally thought to be nondruggable, kinases represent attractive drug targets for pharmaceutical companies and academia. To date, there are over 40 kinase inhibitors approved by the US FDA, with 32 of these being small molecules, in addition to the three mammalian target of rapamycin inhibitor macrolides (sirolimus, temsirolimus and everolimus). Despite the rapid development of kinase inhibitors for cancer, presently none of these agents are approved for CNS indications. This mini perspective highlights selected kinase targets for CNS disorders, of which brain-permeable small-molecule inhibitors are reported, with demonstrated preclinical proof-of-concept efficacy. This is followed by a brief discussion on the key challenges of blood-brain barrier penetration and selectivity profiles in developing kinase inhibitors for CNS disorders.
School of Pharmacy, Faculty of Health Sciences, Curtin University, Bentley, Perth, WA 6102, Australia.
Hendra
H
Gunosewoyo
Shanghai Engineering Research Center of Molecular Therapeutics & New Drug Development, School of Chemistry & Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China.
Lifang
L
Yu
School of Medical Sciences, University of Sydney, NSW 2006, Australia.
Lenka
L
Munoz
School of Chemistry, University of Sydney, NSW 2006, Australia.
Michael
M
Kassiou
D000818:Animals; D001812:Blood-Brain Barrier; D001927:Brain Diseases / Q000188:drug therapy*; D001932:Brain Neoplasms / Q000188:drug therapy; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use
D047428:Protein Kinase Inhibitors
GSK-3; LRRK2; blood–brain barrier; brain cancer; dual-specificity kinase inhibitors; kinase; neurodegenerative diseases