Editors Letter pubs.acs.org/acschemicalbiology
Special Issue Focused on Two Areas Pertinent to Chemical Biology: Post-Translational Modifications and New Frontiers on Kinases
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The success of molecularly targeted cancer therapeutics in tumors has boosted the field of kinase inhibitor research and resulted in the development and approval of an impressive number of drugs. The routine clinical use of kinase inhibitors has not only resulted in a better understanding of kinase regulation in disease states but also disclosed clinically relevant liabilities of these drugs. Battling acquired drug resistance with second- and third-generation kinase inhibitors, paradoxical pathway activation, and off-target inhibition are the focus of modern drug discovery. In this issue, Oliver Hantschel focuses on these aspects and highlights how the methodological advancement of omics-technologies has resulted in a better appreciation of the mode of action of clinical kinase inhibitors. Unique modes of action lead to the discovery of unexpected inhibitor induced pathway activation. 1 Kinase inhibitor selectivity and the knowledge about off-targets is not only an issue in drug discovery, it is also of utmost importance in chemical biology and cellular biology research. One of the pioneers of kinase inhibitor proteomics is Henrik Daub. In his review, he describes how recent developments in quantitative mass spectrometry have enabled for the first time an unbiased view on kinase inhibitor selectivity in the biological context. He also shows how proteome-wide phosphorylation analyses upon kinase inhibitor treatment helps to identify signal transduction pathway and network regulation in complex cellular systems.2 Protein kinases possess a highly dynamic architecture. Against this background, the knowledge about the unique conformational plasticity’s of any given kinase may allow for the development of highly selective inhibitors.3 In his review, Markus Seeliger explores how chemical entities, which are selective for specific kinase conformations, are helpful to obtain individual snapshots of kinase conformational plasticity. He also shows how structural information is complemented by thermodynamic data from inhibitor binding experiments and computational simulations to draw a more complete picture of the dynamic nature of kinases.4 The majority of known kinase inhibitors are ATP-competitive and target the ATP binding site. Inhibitors, which are substrate-competitive, are sparse but nonetheless represent a promising strategy in tackling kinase inhibitor selectivity and to result in better agreement between biochemical and in vitro potency. Matthew Soellner and Meghan Breen survey reported substrate phosphorylation site inhibitors and methods that can be applied to the discovery of such inhibitors.5 They also discuss the challenges inherent to these screening methods. G protein-coupled receptors are among the most common drug targets of currently marketed drugs. So it is not surprising that the research about the pharmacological perturbation of GPCR kinases (GRKs) that initiate the desensitization of active GPCRs is picking up momentum. In their review article, Kristoff Homan and John Tesmer analyze the molecular basis for small molecule
odulating and understanding post-translational modifications are at the heart of chemical biology research. Therefore, we are particularly happy to present to you a “double” special issue centered around this topic. Both parts of this issue contain a fantastic bundle of informative and timely review articles. The Post-Translational Modifications section of this special issue focuses on the broad nature of post-translational modification. Mass spectrometry is certainly one of the key technologies to dissect the combinatorial diversity of posttranslational modifications9 found in biological systems. Al Burlingame highlights how enrichment strategies and highperformance instrumentation coupled with bioinformatics algorithms and scoring strategies advanced the field. He also discusses how this will assist us in annotating the 250 000 PTM sites identified in the human genome to biology.10 Mason Appel and Carolyn Bertozzi focus in their review on formylglycine a unique post-translational modification that is a substantial element in the catalytic mechanism of sulfatases.11 Four reviews are dedicated to the emerging field of histone modification and epigenetics. John Denu and his colleagues summarize recent studies of the molecular mechanisms involved in metabolic regulation of histone modifications.12 The discovery and characterization of chemical probes for deciphering the physiological role of histone methyltransferases are in the focus of the review by Ü mit Kaniskan and Jian Jin.13 The need for high-quality chemical probes for investigating the complex biology of lysine acetyltransferases is explored in the article by Jordan Meier and his team.14 Acetylated histones interact with bromodomains. This finding is instrumental in reading and understanding the “histone code”. Small molecule inhibitors of bromodomain-acetyl-lysine interactions are the topic of the review by Stuart Conway.15 Semisynthetic approaches such as expressed protein ligation (EPL) were instrumental to grasp prenylation.16 Prenylation is essential for the proper cellular activity of numerous proteins including the proto-oncogene RAS. Charuta Palsuledesai and Mark Distefano review the biochemistry of the prenyltransferases and give an account of the current status of prenyltransferase inhibitors as potential therapeutics against several diseases such as cancer.17 Christian Hedberg and Aymelt Itzen complete the issue on post-translational modifications with an exciting story about a recently rediscovered post-translational modification. Adenylylation, the transfer of adenosine monophosphate to mammalian proteins, is particularly interesting when it comes to bacterial infections. The authors also present an overview of screening approaches for inhibiting adenylylation.18 The special issue section New Frontiers on Kinases is a crossjournal collaboration with Biochemistry, Journal of Medicinal Chemistry, and ACS Medicinal Chemistry Letters and highlights the interdisciplinary work that is needed to address and understand this target class. © 2015 American Chemical Society
Published: January 16, 2015 1
DOI: 10.1021/acschembio.5b00010 ACS Chem. Biol. 2015, 10, 1−2
ACS Chemical Biology
Editors Letter
(10) Burlingame, A. L. (2014) Mass spectrometry-based detection and assignment of protein post-translational modifications. ACS Chem. Biol., DOI: 10.1021/cb500904b. (11) Appel, M. J., and Bertozzi, C. R. (2014) Formylglycine, a posttranslationally generated residue with unique catalytic capabilities and biotechnology applications. ACS Chem. Biol., DOI: 10.1021/ cb500897w. (12) Fan, J., Krautkramer, K. A., Feldman, J. L., and Denu, J. M. (2015) Metabolic regulation of histone post-translational modifications. ACS Chem. Biol., DOI: 10.1021/cb500846u. (13) Kaniskan, H. U., and Jin, J. (2014) Chemical probes of histone lysine methyltransferases. ACS Chem. Biol., DOI: 10.1021/cb500785t. (14) Montgomery, D. C., Sorum, A. W., and Meier, J. L. (2015) Defining the orphan functions of lysine acetyltransferases. ACS Chem. Biol., DOI: 10.1021/cb500853p. (15) Conway, S. J. (2014) Small molecule inhibitors of bromodomain-acetyl-lysine interactions. ACS Chem. Biol., DOI: 10.1021/cb500996u. (16) Rauh, D., and Waldmann, H. (2007) Linking chemistry and biology for the study of protein function. Angew. Chem. 46 (6), 826−9. (17) Palsuledesai, C. C., and Distefano, M. D. (2014) Protein prenylation: Enzymes, therapeutics, and biotechnology applications. ACS Chem. Biol., DOI: 10.1021/cb500791f. (18) Hedberg, C., and Itzen, A. (2014) Molecular perspectives on protein adenylylation. ACS Chem. Biol., DOI: 10.1021/cb500854e.
inhibition of GRKs and present key drivers of potency and selectivity among GRK inhibitors.6 The development and application of small molecules to perturb protein function to validate/invalidate potential drug targets and to understand better the dynamics of complex biological systems is a major topic in modern chemical biology. However, meaningful perturbation experiments always require potent and selective inhibitors. A target class, where high-quality functional probes are desperately needed but fall short, is sphingosine kinases. These lipid kinases generate small signaling molecules, which have been linked to cancer and fibrosis. Webster Santos and Kevin Lynch explore the druggability of these interesting transferases and highlight the need for developing next generation functional probes.7 Targeting kinases in pathogens is a promising strategy to interfere, for example, with virulence or antibiotic resistance. In their review “Bacterial Histidine Kinases as Novel Antibacterial Drug Targets” Jerry Wells and colleagues discuss the biological importance of histidine kinases (HK) as the main signal transduction pathways and in the bacterial two-component systems (TCS). The authors also present a number of published TCS and HK inhibitors as potential starting points for structure-based approaches to developing novel antibacterials.8 I hope you enjoy reading these reviews as much as I have.
Daniel Rauh*
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Technische Universität Dortmund, Fakultät für Chemie und Chemische Biologie, Otto-Hahn-Strasse 6, D-44227 Dortmund, Germany
AUTHOR INFORMATION
Corresponding Author
*Phone: +49 (0)231-755 7080. Fax: +49 (0)231-755 7082. Email:
[email protected]. Notes
Views expressed in this editorial are those of the author and not necessarily the views of the ACS.
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REFERENCES
(1) Hantschel, O. (2015) Unexpected off-targets and paradoxical pathway activation by kinase inhibitors. ACS Chem. Biol., DOI: 10.1021/cb500886n. (2) Daub, H. (2014) Quantitative proteomics of kinase inhibitor targets and mechanisms. ACS Chem. Biol., DOI: 10.1021/cb5008794. (3) Fang, Z., Grütter, C., and Rauh, D. (2013) Strategies for the selective regulation of kinases with allosteric modulators: Exploiting exclusive structural features. ACS Chem. Biol. 8 (1), 58−70. (4) Tong, M., and Seeliger, M. A. (2014) Targeting conformational plasticity of protein kinases. ACS Chem. Biol., DOI: 10.1021/ cb500870a. (5) Breen, M. E., and Soellner, M. B. (2014) Small molecule substrate phosphorylation site inhibitors of protein kinases: Approaches and challenges. ACS Chem. Biol., DOI: 10.1021/ cb5008376. (6) Homan, K. T., and Tesmer, J. J. (2014) Molecular basis for small molecule inhibition of G protein-coupled receptor kinases. ACS Chem. Biol., DOI: 10.1021/cb5003976. (7) Santos, W. L., and Lynch, K. R. (2014) Drugging sphingosine kinases. ACS Chem. Biol., DOI: 10.1021/cb5008426. (8) Bem, A. E., Velikova, N., Pellicer, M. T., Baarlen, P. V., Marina, A., and Wells, J. M. (2014) Bacterial histidine kinases as novel antibacterial drug targets. ACS Chem. Biol., DOI: 10.1021/cb5007135. (9) Venter, J. C., et al. (2001) The sequence of the human genome. Science 291 (5507), 1304−51. 2
DOI: 10.1021/acschembio.5b00010 ACS Chem. Biol. 2015, 10, 1−2
