Discovery of protein phosphatase inhibitor classes by biology-oriented synthesis

Abstract

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...

Biology-inspired synthesis of compound libraries

“…The natural product space therefore is enriched with bioactive structures and thus contains promising starting points for the search of new bioactive molecules. Consequently, Waldmann and coworkers [27] forged these complementary properties of bioactive small molecules (either natural products or known drugs) and their protein targets (receptors, proteins, transporters, etc.) into a new concept for library synthesis, termed BIOS.…”

“…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.…”

“…In addition, several libraries based on natural product scaffolds have been screened for enzyme inhibition. Figure 9D shows a representative example that was derived from an indoloquinolizidine compound library and exerts potent inhibition of the phosphatase MptpB of Mycobacterium tuberculosis [27].…”

“…A merging of these two approaches into one concept, i.e., BIOS, leads to synergistic effects, providing, for example, an approach to simplify structures of known inhibitors while retaining their basic biological activity [27,37,40,51]. The scaffold tree approach arranges scaffolds of natural products in a tree-like structure with the inner segments of the tree representing less complex scaffolds.…”

“…Moreover, extending the screen to other phosphatases allowed the elucidation of structurally new inhibitors of the M. tuberculosis protein tyrosine phosphatase B (MPTPB) from the same library. Structurally simpler compounds with three-and two-membered rings also yielded another inhibitor of Cdc25A with a similar IC 50 value as the natural products and also contained an inhibitor of the protein tyrosine phosphatase 1B (PTP1B) and eight inhibitors of MPTPB in the submicromolar range [27,51]. A more elaborate set of rules was developed by Schuffenhauer et al [91], which consists of 13 rules and was designed to reflect more the thinking of a medicinal chemist.…”