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Disease mechanisms and emerging therapies: protein kinases and their inhibitors in myocardial disease

Nature Clinical Practice Cardiovascular Medicine volume 3, pages 437–445 (2006)Cite this article

Abstract

Most clinically validated drugs for treating patients with cardiovascular disease target G-protein-coupled receptors (GPCRs) in the cell membrane. GPCRs engage and activate multiple intracellular signaling cascades, which are regulated by serine/threonine protein kinases. These protein kinases are cytoplasmic, more abundant than GPCRs, and have rapidly emerged as drug targets in cardiovascular diseases. One exciting potential advantage to targeting serine/threonine protein kinases rather than GPCRs is the capability of influencing more precisely the diverse biological responses that are initiated by a common GPCR. On the other hand, highly specific targeting of individual protein kinases for drug therapy presents some medicinal chemistry challenges. This concise review focuses on the biology of serine/threonine protein kinases in the cardiovascular system, discusses the current state of protein kinase inhibitor drug development for myocardial diseases, and illustrates some of the unique medicinal chemistry considerations in targeting protein kinases.

Key Points

  • Despite abundance, interest in targeting protein kinases for myocardial disease developed later than that for G-protein-coupled receptors

  • In myocardial diseases overexpression of protein kinases can recapitulate clinically important disease phenotypes, while inhibition of protein kinases can reduce susceptibility

  • Potential strategies for protein kinase inhibition include competition for ATP binding, prevention of 'anchoring' to target proteins, and sterically induced reduction in ATP binding affinity and stabilization of inactive conformations

  • A potential advantage for targeting protein kinases over G-protein-coupled receptors is improved biological specificity, but this feature remains to be validated clinically

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Figure 1: Activation of protein kinases by cell-membrane receptors, and signaling network interactions leading to cardiovascular disease phenotypes.
Figure 2: Schematic representation of activation of a protein kinase as illustrated by CaMKII.

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Author information

Authors and Affiliations

  1. Director of Cardiology and Associate Director of the Cardiovascular Research Center at the University of Iowa, Iowa City, IA, USA

    Mark E Anderson

  2. Senior Director of Research at Scios Inc., Fremont, CA, USA

    Linda S Higgins

  3. Vice President of PPD Biomarker Discovery Sciences, Menlo Park, CA, USA

    Howard Schulman

Authors
  1. Mark E Anderson
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  2. Linda S Higgins
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  3. Howard Schulman
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Corresponding author

Correspondence to Mark E Anderson.

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Competing interests

Mark E Anderson and Howard Shulman are named inventors on a patent to treat cardiac arrhythmias by CaMKII inhibition.

Linda S Higgins directs drug development and efforts to inhibit kinases, including studies into CaMKII, at Scios Inc., Fremont, CA, USA.

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Anderson, M., Higgins, L. & Schulman, H. Disease mechanisms and emerging therapies: protein kinases and their inhibitors in myocardial disease. Nat Rev Cardiol 3, 437–445 (2006). https://doi.org/10.1038/ncpcardio0585

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