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TitleDefining the Neural Kinome: Strategies and Opportunities for Small Molecule Drug Discovery to Target Neurodegenerative Diseases.
Publication TypeJournal Article
Year of Publication2020
AuthorsKrahn, Andrea I., Carrow Wells, David H. Drewry, Lenore K. Beitel, Thomas M. Durcan, and Alison D. Axtman
JournalACS Chem Neurosci
Volume11
Issue13
Pagination1871-1886
Date Published2020 07 01
ISSN1948-7193
Abstract

Kinases are highly tractable drug targets that have reached unparalleled success in fields such as cancer but whose potential has not yet been realized in neuroscience. There are currently 55 approved small molecule kinase-targeting drugs, 48 of which have an anticancer indication. The intrinsic complexity linked to central nervous system (CNS) drug development and a lack of validated targets has hindered progress in developing kinase inhibitors for CNS disorders when compared to other therapeutic areas such as oncology. Identification and/or characterization of new kinases as potential drug targets for neurodegenerative diseases will create opportunities for the development of CNS drugs in the future. The track record of kinase inhibitors in other disease indications supports the idea that with the best targets identified small molecule kinase modulators will become impactful therapeutics for neurodegenerative diseases. This Review highlights the imminent need for new therapeutics to treat the most prevalent neurodegenerative diseases as well as the promise of kinase inhibitors to address this need. With a focus on kinases that remain largely unexplored after decades of dedicated research in the kinase field, we offer specific examples of understudied kinases that are supported by patient-derived data as linked to Alzheimer's disease, Parkinson's disease, and/or amyotrophic lateral sclerosis. Finally, we show literature-reported high-quality inhibitors for several understudied kinases and suggest other kinases that merit additional medicinal chemistry efforts to elucidate their therapeutic potential.

DOI10.1021/acschemneuro.0c00176
Alternate JournalACS Chem Neurosci
PubMed ID32464049
Grant ListU24 DK116204 / DK / NIDDK NIH HHS / United States
U54 AG065187 / AG / NIA NIH HHS / United States
106169/ZZ14/Z / WT_ / Wellcome Trust / United Kingdom