Synthesis and Biological Evaluation of an Indomethacin Library Reveals a New Class of Angiogenesis‐Related Kinase Inhibitors

Rosenbaum, Claudia; Baumhof, Patrick; Mazitschek, Ralf; Müller, Oliver; Giannis, Athanassios; Waldmann, Herbert

doi:10.1002/anie.200352582

Cited by 58 publications

(12 citation statements)

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“…Systematic synthetic efforts and biochemical investigations led to the finding that the indomethacin core scaffold defines a new class of kinase inhibitors (Rosenbaum et al, 2004).…”

Section: Bios Libraries Yield Small Molecule Probes For Different Biomentioning

confidence: 99%

Principles, implementation, and application of biology-oriented synthesis (BIOS)

Wilk¹,

Zimmermann²,

Kaiser

et al. 2010

Biological Chemistry

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Biology-oriented synthesis (BIOS) represents an alternative approach for the generation of compound collections for biological applications. In BIOS, biologically relevant and prevalidated scaffold structures, such as core structures of natural products or known drugs, are employed as scaffolds for the generation of compound collections with focused diversity. In this review, we discuss the underlying concept of the BIOS approach, and its practical implementation in library design and synthesis. To highlight its relevance for chemical biology applications, we finally present examples in which compound collections generated under the BIOS principle have been used to elucidate biological questions.

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“…Systematic synthetic efforts and biochemical investigations led to the finding that the indomethacin core scaffold defines a new class of kinase inhibitors (Rosenbaum et al, 2004).…”

Section: Bios Libraries Yield Small Molecule Probes For Different Biomentioning

confidence: 99%

Principles, implementation, and application of biology-oriented synthesis (BIOS)

Wilk¹,

Zimmermann²,

Kaiser

et al. 2010

Biological Chemistry

Self Cite

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“…Moreover, it allows a correlation of different scaffold classes as performed during BIOS (see the BIOS section for more details). Based on this tree, Waldmann and coworkers synthesized libraries featuring spiroketal [32 -34], a,b-unsaturated lactone [35 -40], tetrahydropyrane [41,42], indolactam [43,44], decaline [45 -48], indole scaffolds [49,50] and indoloquinolizidine [27,51], and proved their biological activity in various screening campaigns, thereby validating the scaffold tree approach as a powerful method for generating libraries with high contents of biologically active molecules. For example, two cell-based screens of a library consisting of only 50 a,b-unsaturated d-lactones yielded small molecule modulators of cell cycle progression (Fig.…”

Section: Kaiser Et Almentioning

confidence: 99%

Biology-inspired synthesis of compound libraries

Kaiser

Wetzel

Kumar

et al. 2008

Cell. Mol. Life Sci.

148

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“…Accordingly, a collection of 188 compounds containing examples for both scaffold structures and synthesized as described earlier (19,20) was investigated for inhibition of the seven phosphatases in the screen. Again, two compounds with potency for Cdc25A inhibition similar to the guiding NPs and the tetracyclic compounds were identified.…”

Section: Discussionmentioning

confidence: 99%

Discovery of protein phosphatase inhibitor classes by biology-oriented synthesis

Nören‐Müller

Reis‐Corrêa

Prinz

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Protein phosphatases have very recently emerged as important targets for chemical biology and medicinal chemistry research, and new phosphatase inhibitor classes are in high demand. The underlying frameworks of natural products represent the evolutionarily selected fractions of chemical space explored by nature so far and meet the criteria of relevance to nature and biological prevalidation most crucial to inhibitor development. We refer to synthesis efforts and compound collection development based on these criteria as biology-oriented synthesis. For the discovery of phosphatase inhibitor classes by means of this approach, four natural product-derived or -inspired medium-sized compound collections were synthesized and investigated for inhibition of the tyrosine phosphatases VE-PTP, Shp-2, PTP1B, MptpA, and MptpB and the dual-specificity phosphatases Cdc25A and VHR. The screen yielded four unprecedented and selective phosphatase inhibitor classes for four phosphatases with high hit rates. For VE-PTP and MptpB the first inhibitors were discovered. These results demonstrate that biology-oriented synthesis is an efficient approach to the discovery of new compound classes for medicinal chemistry and chemical biology research that opens up new opportunities for the study of phosphatases, which may lead to the development of new drug candidates.chemical biology ͉ medicinal chemistry ͉ phosphatase inhibition P rotein phosphatases are key regulators of innumerable biological processes (1, 2). Small-molecule modulators of phosphatase activity have proven to be powerful tools for the study of the chemical biology of these enzymes (3), and, in particular, protein tyrosine phosphatases (PTPs) (4, 5) and dual-specificity phosphatases (6) have recently moved into the focus of a growing number of drug discovery programs, for instance in diabetes and anticancer research. However, although important progress has been made, the development of potent and selective phosphatase inhibitors is still in its early stages, and structurally new phosphatase inhibitor classes are in high demand.Relevance to nature is one of the most important criteria to be met by compound classes for chemical biology and medicinal chemistry research. The underlying frameworks of natural products (NPs) provide evolutionarily selected chemical structures encoding the properties required for binding to proteins, and their structural scaffolds represent the biologically relevant and prevalidated fractions of chemical space explored by nature so far (7-9). Consequently, it is to be expected that compound collections designed on the basis of NP structure will be enriched in biochemical and biological activity. Based on this reasoning, we have introduced a structural classification of natural products (SCONP) in a tree-like arrangement as an idea-and hypothesis-generating tool for the design and synthesis of compound collections (8). It permits the selection of library scaffolds based on relevance to and prevalidation by nature. We refer to synthesis efforts base...

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Synthesis and Biological Evaluation of an Indomethacin Library Reveals a New Class of Angiogenesis‐Related Kinase Inhibitors

Cited by 58 publications

References 38 publications

Principles, implementation, and application of biology-oriented synthesis (BIOS)

Principles, implementation, and application of biology-oriented synthesis (BIOS)

Biology-inspired synthesis of compound libraries

Discovery of protein phosphatase inhibitor classes by biology-oriented synthesis

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