Cycles of depalmitoylation and repalmitoylation critically control the steady-state localization and function of various peripheral membrane proteins, such as Ras proto-oncogene products. Interference with acylation using small molecules is a strategy to modulate cellular localization--and thereby unregulated signaling--caused by palmitoylated Ras proteins. We present the knowledge-based development and characterization of a potent inhibitor of acyl protein thioesterase 1 (APT1), a bona fide depalmitoylating enzyme that is, so far, poorly characterized in cells. The inhibitor, palmostatin B, perturbs the cellular acylation cycle at the level of depalmitoylation and thereby causes a loss of the precise steady-state localization of palmitoylated Ras. As a consequence, palmostatin B induces partial phenotypic reversion in oncogenic HRasG12V-transformed fibroblasts. We identify APT1 as one of the thioesterases in the acylation cycle and show that this protein is a cellular target of the inhibitor.
The identification of small molecules that fall within the biologically relevant subfraction of vast chemical space is of utmost importance to chemical biology and medicinal chemistry research. The prerequirement of biological relevance to be met by such molecules is fulfilled by natural product-derived compound collections. We report a structural classification of natural products (SCONP) as organizing principle for charting the known chemical space explored by nature. SCONP arranges the scaffolds of the natural products in a tree-like fashion and provides a viable analysis-and hypothesis-generating tool for the design of natural product-derived compound collections. The validity of the approach is demonstrated in the development of a previously undescribed class of selective and potent inhibitors of 11-hydroxysteroid dehydrogenase type 1 with activity in cells guided by SCONP and protein structure similarity clustering. 11-hydroxysteroid dehydrogenase type 1 is a target in the development of new therapies for the treatment of diabetes, the metabolic syndrome, and obesity.chemical biology ͉ compound libraries ͉ hydroxysteroid dehydrogenase ͉ cheminformatics T he efficient identification of small molecules that modulate protein function in vitro and in vivo is at the heart of chemical biology and medicinal chemistry research and the development of new therapies and diagnostics for disease. Key to their discovery is the identification and charting of biologically relevant space, i.e., the regions of complete chemical space that are relevant to biology (1-5). The underlying structures of evolutionary selected natural products (NPs) define structural prerequisites for binding to proteins (4, 6). Their structural scaffolds represent the biologically relevant and prevalidated fractions of chemical structure space explored by nature so far. Consequently, the probability that compound libraries designed to mimic the structures and properties of NP classes will be biologically relevant is high, and it is also to be expected that ''NP-guided compound library development'' (1, 4) will prove to be a viable guiding principle for the identification of small molecules for chemical biology and medicinal chemistry research (1-6).A systematic structure-orientated organizing principle of the known NPs combined with annotations of biological origin and pharmacological activity would chart the regions of chemical space explored by nature, provide a structural rationalization and categorization of NP diversity, and also provide guidance for the development of NP-like compound libraries.Statistical analyses of different NP databases have been performed in a few cases (7-10); however, a systematic and annotated structural categorization of NPs leading to development principles for compound library design is missing.Here, we introduce a structural classification of NPs (SCONP) as a idea-and hypothesis-generating tool to define structural relationships between different NP classes in a tree-like arrangement and for the design of NP-de...
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