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  • Review Article
  • Published:

Targeting protein kinases in central nervous system disorders

Nature Reviews Drug Discovery volume 8, pages 892–909 (2009)Cite this article

Key Points

  • The success of drugs such as imatinib has made protein kinases an intensively studied class of drug targets.

  • Research on new protein kinase targets and a range of potential disease indications has led to increasing interest in the development of small-molecule kinase inhibitors for the treatment of central nervous system (CNS) disorders.

  • Although disclosed clinical trial information shows a current oncology focus to CNS clinical investigations, preclinical in vivo studies of protein kinase inhibitors in animal models reveal a major increase in efforts for other CNS disease indications. Selected examples of emerging protein kinase targets for CNS disorders and the state of inhibitor development are discussed in this Review.

  • A crucial issue in CNS drug discovery is the challenge of effective blood–brain barrier (BBB) penetrance. Statistical analysis of a database of 448 disclosed small molecules revealed trends in molecular properties that correlate with in vivo BBB penetrance. Lower molecular weights and polar surface area values were correlated with brain uptake, whereas higher lipophilicity was not. The available information about CNS drug discovery in general, and kinase inhibitor drugs in particular, raises concerns about the approach of applying existing drugs to CNS therapeutic use.

  • Some of the molecular property trends that correlate with good BBB penetrance also correlate with a molecule being a good substrate for the first-pass metabolism enzyme cytochrome P450 2D6 (CYP2D6). Polymorphisms in this enzyme contribute to variability between individuals in drug metabolism. In medicinal chemistry refinement to improve BBB penetrance, care must therefore be taken to avoid generating better CYP2D6 substrates. Currently, 31% of approved CNS drugs are metabolized by CYP2D6.

  • Current CNS-targeted drug discovery programmes use contemporary approaches, such as molecular fragment expansion, that address these issues at the compound design stage and use early drug property and bioavailability screens to generate fewer, more CNS-focused lead compounds.

Abstract

Protein kinases are a growing drug target class in disorders in peripheral tissues, but the development of kinase-targeted therapies for central nervous system (CNS) diseases remains a challenge, largely owing to issues associated specifically with CNS drug discovery. However, several candidate therapeutics that target CNS protein kinases are now in various stages of preclinical and clinical development. We review candidate compounds and discuss selected CNS protein kinases that are emerging as important therapeutic targets. In addition, we analyse trends in small-molecule properties that correlate with key challenges in CNS drug discovery, such as blood–brain barrier penetrance and cytochrome P450-mediated metabolism, and discuss the potential of future approaches that will integrate molecular-fragment expansion with pharmacoinformatics to address these challenges.

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Figure 1: Trends in drug discovery and development efforts targeting protein kinases.
Figure 2: Selected chemical structures of small-molecule kinase inhibitors in clinical trials for CNS indications.
Figure 3: Protein kinase targets as components of intracellular signal transduction networks.
Figure 4: Key molecular-property trends for small molecules.
Figure 5: Structure of the protein kinase catalytic core and bound inhibitor in the ATP fold.
Figure 6: Example of a potential compound discovery paradigm for CNS kinase targets.

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Acknowledgements

The authors acknowledge funding from the National Institutes of Health (AG031311, NS056051 and AG013939).

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Authors and Affiliations

  1. Center for Molecular Innovation and Drug Discovery, Northwestern University, Chicago, 60611, Illinois, USA

    Laura K. Chico, Linda J. Van Eldik & D. Martin Watterson

  2. LKC Pharma Services, Inc., LaGrange, 60525, Illinois, USA

    Laura K. Chico

  3. Department of Cell and Molecular Biology Feinberg School of Medicine, Northwestern University, Chicago, 60611, Illinois, USA

    Linda J. Van Eldik

  4. Department of Molecular Pharmacology and Biological Chemistry, Feinberg School of Medicine, Northwestern University, Chicago, 60611, Illinois, USA

    D. Martin Watterson

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  1. Laura K. Chico
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Correspondence to D. Martin Watterson.

Supplementary information

Supplementary information S1 (box)

Supplementary information (PDF 1093 kb)

Supplementary information S2 (table)

Database of protein kinase targets for CNS indications (XLS 62 kb)

Supplementary information S3 (table)

Database of disclosed CNS-penetrant small molecules (XLS 156 kb)

Supplementary information S4 (table)

Small molecule protein kinase inhibitor drugs (approved and in clinical trial) (XLS 28 kb)

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Glossary

Blood–brain barrier

The barrier formed by tight junctions of brain endothelial cells that restrict the passage of drugs between the bloodstream and the brain.

Pharmacodynamics

The biochemical and physiological effects of an administered drug on the body, and the relationships between drug dose and efficacy or toxicity.

Kinome

The subset of genes that encode protein kinases in the genome of an organism.

P-glycoprotein

An efflux transporter at the blood–brain barrier that can prevent drug substrate accumulation in the brain.

Polar surface area

The total surface area of all polar atoms (usually oxygen and nitrogen), including attached hydrogen ions.

LogP

A measure of a drug's lipophilicity, it is the logarithm of the octanol–water partition coefficient. Higher values are associated with greater lipophilicity, whereas lower values are characteristic of more water-soluble compounds.

LogBB

The steady-state ratio of drug concentration in the brain versus drug concentration in the blood.

Pharmacokinetics

'What the body does to the drug', including the extent and rate of drug absorption, distribution, metabolism and excretion.

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Chico, L., Van Eldik, L. & Watterson, D. Targeting protein kinases in central nervous system disorders. Nat Rev Drug Discov 8, 892–909 (2009). https://doi.org/10.1038/nrd2999

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