Editors Letter pubs.acs.org/acschemicalbiology
A Special Thematic Compilation/Special Issue Crossover with Biochemistry, Journal of Medicinal Chemistry, and ACS Medicinal Chemistry Letters Focused on Kinases inhibitors that are isoform-specific.4 Such molecular tools will be key for understanding the isoform-specific mechanisms of JNK signaling. Covalent and irreversible kinase inhibitors are receiving major attention recently. The clinical success stories of afatinib and ibrutinib in targeting genetically defined tumors have proven that covalent kinase inhibitors are indeed biocompatible. Matthew Soellner targets the tyrosine kinase c-Src with covalent inhibitors. In his study, he presents a general framework for generating selective irreversible inhibitors from reversible, promiscuous inhibitor scaffolds.5 The selective modulation of kinase function remains a major challenge in kinase inhibitor research. The group of Dustin Maly addresses this issue by combining classic ATP-competitive inhibitors with an engineered form of a self-labeling protein (SNAP-tag).6 The resulting bivalent inhibitors are superior in selectivity and suitable for applications in living cells. A major challenge in chemical-biology research is the generation and definition of high-quality, selective chemical probes with known pharmacology that qualify for the dissection of protein function in cellular systems. Nathanael Gray and Andrea Musacchio present a series of pyrimido benzodiazepines as a novel class of Aurora kinase inhibitors.7 These highly potent and selective compounds were discovered from a phenotypic cellular screen and may serve as valuable probes of Aurora-dependent functions. Selectivity in targeting kinases is also the topic of a recent review article. Fang et al. focus on allosteric kinase modulation and highlight how targeting exclusive structural features can be successfully exploited for the development of modulators to explore kinase function beyond catalysis.8 We hope you enjoy reading these papers and get rich insights into kinases and the connected chemical biology research.
ACS Chemical Biology is sending out a broad call for manuscripts (Reviews, Letters, and Articles) for a special issue focused on all aspects of kinase biology and kinase inhibitor research. The upcoming special issue will be a crossjournal initiative between Biochemistry, Journal of Medicinal Chemistry, ACS Medicinal Chemistry Letters, and ACS Chemical Biology, with a focus on the biology, pharmacology, and medicinal chemistry of one of the most prominent target enzyme classes − kinases. We aim to publish the special issue in January 2015, and therefore all submissions must be received no later than September 1, 2014 for inclusion. When submitting a manuscript, please be sure to click on the Special Issues dropdown box and select ″New Frontiers on Kinases″ in our submission system. If you are unsure of which journal to submit to, please send a presubmission inquiry (which should include a cover letter and abstract) to
[email protected]. We would be happy to assist you with picking an appropriate journal. Two decades of extensive kinase research have provided a detailed understanding of the principles of kinase signaling and fostered the discovery and development of a substantial number of kinase inhibitors of various types. Today, kinase research is multidisciplinary and ranges from pure organic and peptide synthesis to structural and cellular biology. Chemical biology research often utilizes the systematic application of small molecules to perturb kinase function in cells to better understand the dynamic composition of biological systems. Such probe molecules are not only useful tools in cell biology, they may also serve as starting points for lead-optimization and drug development. There are currently two-dozen kinase inhibitor drugs approved for clinical use. In the past couple of years, protein kinases are the single most successful target class based on the number of approvals by the FDA.1 More importantly, the success of molecularly targeted cancer therapeutics in tumors with specific mutations has challenged the lack of progress through conventional cytotoxic chemotherapy. Thus, personalized cancer treatment has become a reality in the care of patients, exemplified by the growing number of tumors that are dependent on mutant kinases and thereby amenable to such approaches (e.g., EGFR- and Alk mutant lung cancer, BRAF mutant melanoma).2 However, the complex regulation of kinase function and biology, the liability to off-target inhibition, acquired drug resistance, etc. call for the need for novel tools and improved targeted inhibitors in kinase research. In this cross-issue, the group of Terrence Burke presents a study to target polo-like kinase 1 function by inhibiting protein−protein interactions of the polo-box domain.3 The inhibition of kinase function by peptidic structures is also the focus of Andreas Plückthun and colleagues. They facilitate designed ankyrin repeat proteins (DARPins) as a powerful way for generating intracellular c-Jun N-terminal kinase (JNK) © 2014 American Chemical Society
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Daniel Rauh, Associate Editor, ACS Chemical Biology
AUTHOR INFORMATION
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) Mullard, A. (2013) 2012 FDA drug approvals. Nat. Rev. Drug Discovery 12, 87−90. (2) Heuckmann, J. M., Rauh, D., and Thomas, R. K. (2012) Epidermal growth factor receptor (EGFR) signaling and covalent EGFR inhibition in lung cancer. J. Clin. Oncol. 30, 3417−3420. (3) Liu, F., Park, J. E., Qian, W. J., Lim, D., Scharow, A., Berg, T., Yaffe, M. B., Lee, K. S., and Burke, T. R., Jr. (2012) Identification of high affinity polo-like kinase 1 (Plk1) polo-box domain binding peptides using oxime-based diversification. ACS Chem. Biol. 7, 805− 810. (4) Parizek, P., Kummer, L., Rube, P., Prinz, A., Herberg, F. W., and Pluckthun, A. (2012) Designed ankyrin repeat proteins (DARPins) as Published: March 21, 2014 579
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ACS Chemical Biology
Editors Letter
novel isoform-specific intracellular inhibitors of c-Jun N-terminal kinases. ACS Chem. Biol. 7, 1356−1366. (5) Kwarcinski, F. E., Fox, C. C., Steffey, M. E., and Soellner, M. B. (2012) Irreversible inhibitors of c-Src kinase that target a nonconserved cysteine. ACS Chem. Biol. 7, 1910−1917. (6) Hill, Z. B., Perera, B. G., Andrews, S. S., and Maly, D. J. (2012) Targeting diverse signaling interaction sites allows the rapid generation of bivalent kinase inhibitors. ACS Chem. Biol. 7, 487−495. (7) Kwiatkowski, N., Deng, X., Wang, J., Tan, L., Villa, F., Santaguida, S., Huang, H. C., Mitchison, T., Musacchio, A., and Gray, N. (2012) Selective aurora kinase inhibitors identified using a taxol-induced checkpoint sensitivity screen. ACS Chem. Biol. 7, 185−196. (8) Fang, Z., Grutter, C., and Rauh, D. (2013) Strategies for the selective regulation of kinases with allosteric modulators: exploiting exclusive structural features. ACS Chem. Biol. 8, 58−70.
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