4.6 Review

Defining the Neural Kinome: Strategies and Opportunities for Small Molecule Drug Discovery to Target Neurodegenerative Diseases

期刊

ACS CHEMICAL NEUROSCIENCE
卷 11, 期 13, 页码 1871-1886

出版社

AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.0c00176

关键词

kinase; neurodegeneration; CNS; Alzheimer's disease; Parkinson's disease; amyotrophic lateral sclerosis; KCGS; GWAS; SNP; IDG; SGC; iPSCs

资金

  1. AbbVie [1097737]
  2. Bayer Pharma AG
  3. Boehringer Ingelheim
  4. Canada Foundation for Innovation
  5. Eshelman Institute for Innovation
  6. Genome Canada
  7. Genentech
  8. Innovative Medicines Initiative (EU/EFPIA) [ULTRA-DD] [115766]
  9. Janssen
  10. Merck KGaA Darmstadt Germany
  11. MSD
  12. Novartis Pharma AG
  13. Ontario Ministry of Economic Development and Innovation
  14. Pfizer
  15. Sao Paulo Research Foundation-FAPESP [2013/50724-5]
  16. Takeda
  17. Wellcome [106169/ZZ14/Z]
  18. ALSA Investigator Initiated Starter Grant [wa1127, U54AG065187]
  19. Ghislaine and Sebastian Van Berkom foundation
  20. McGill Healthy Brains for Healthy Lives
  21. [U24DK116204]

向作者/读者索取更多资源

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 oncolo 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.

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