Kinase targets in CNS drug discovery
MetadataShow full item record
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.
Showing items related by title, author, creator and subject.
A novel inhibitor of the PI3K/Akt pathway based on the structure of inositol 1,3,4,5,6-pentakisphosphateFalasca, Marco; Chiozzotto, D.; Godage, H.; Mazzoletti, M.; Riley, A.; Previdi, S.; Potter, B.; Broggini, M.; Maffucci, T. (2010)Background: Owing to its role in cancer, the phosphoinositide 3-kinase (PI3K)/Akt pathway is an attractive target for therapeutic intervention. We previously reported that the inhibition of Akt by inositol 1,3,4,5,6- ...
Small molecule sensitization to TRAIL is mediated via nuclear localization, phosphorylation and inhibition of chaperone activity of Hsp27Mellier, G.; Liu, D.; Bellot, G.; Lisa Holme, A.; Pervaiz, Shazib (2013)The small chaperone protein Hsp27 confers resistance to apoptosis, and therefore is an attractive anticancer drug target. We report here a novel mechanism underlying the tumor necrosis factor-related apoptosis-inducing ...
Systematic chemical and molecular profiling of MLL-rearranged infant acute lymphoblastic leukemia reveals efficacy of romidepsinCruickshank, M.; Ford, J.; Cheung, Laurence; Heng, J.; Singh, S.; Wells, J.; Failes, T.; Arndt, G.; Smithers, N.; Prinjha, R.; Anderson, D.; Carter, K.; Gout, A.; Lassmann, T.; O'Reilly, J.; Cole, C.; Kotecha, R.; Kees, U. (2017)To address the poor prognosis of mixed lineage leukemia (MLL)-rearranged infant acute lymphoblastic leukemia (iALL), we generated a panel of cell lines from primary patient samples and investigated cytotoxic responses to ...