Biomedical subjects

Jason C Wong

Publications and source records attributed to Jason C Wong.

6 recordsLinked to original sources

PubMed2004

Modular synthesis and preliminary biological evaluation of stereochemically diverse 1,3-dioxanes.

Modular synthesis and substrate stereocontrol were combined to furnish 18,000 diverse 1,3-dioxanes whose distribution in chemical space rivals that of a reference set of over 2,000 bioactive small molecules. Library quality was assessed at key synthetic stages, culminating in a detailed postsynthesis analysis of purity, yield, and structural characterizability, and the resynthesis of library subsets that did not meet quality standards. The importance of this analysis-resynthesis process is highlighted by the discovery of new biological probes through organismal and protein binding assays, and by determination of the building block and stereochemical basis for their bioactivity. This evaluation of a portion of the 1,3-dioxane library suggests that many additional probes for chemical genetics will be identified as the entire library becomes biologically annotated.

Amines↗

PubMed2004

Mapping chemical space using molecular descriptors and chemical genetics: deacetylase inhibitors.

An objective of chemical genetics is to understand the relationships between the structures of small molecules and their phenotypic effects in intact living systems. We present here the results of a global analysis of a molecular descriptor space constructed using structural descriptors of an aryl 1,3-dioxane-based diversity-oriented synthesis-derived library containing structural biasing elements directed at inhibiting protein deacetylases. Using principal component analysis and three-dimensional visualization, we generated metric space maps with morphological features contributed by different diversity elements within the library. Filtering these maps using phenotypic descriptors derived from measurements of small-molecule activities in an array of cell-based assays revealed different densities of biological activity within specific subspaces. These results provide evidence that certain structural features may be important for conferring potency and selectivity on deacetylase inhibitors with respect to tubulin and histone acetylation. Moreover, these results highlight an example of the importance of using functional measures to assess molecular diversity. Similar analyses of other chemical spaces and activity classes promise to facilitate the development of chemical genetics.

Amidohydrolases↗

PubMed2003

Structural biasing elements for in-cell histone deacetylase paralog selectivity.

We use the structural dissection of two 1,3-dioxanes with in-cell histone deacetylase (HDAC) paralog selectivity to identify key elements for selective HDAC inhibitors. We demonstrate that o-aminoanilides are inactive toward HDAC6 while apparently inhibiting deacetylases that act upon histone substrates. This finding has important clinical implications for the development of HDAC inhibitor-based treatments that do not interfere with microtubule dynamics associated with HDAC6. We also show that suberoylanilide hydroxamic acid (SAHA) alone is a nonparalog-selective HDAC inhibitor and that the 1,3-dioxane diversity appended to SAHA is essential for HDAC6 paralog selectivity.

Anilides↗

PubMed2003

Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation.

Protein acetylation, especially histone acetylation, is the subject of both research and clinical investigation. At least four small-molecule histone deacetylase inhibitors are currently in clinical trials for the treatment of cancer. These and other inhibitors also affect microtubule acetylation. A multidimensional, chemical genetic screen of 7,392 small molecules was used to discover "tubacin," which inhibits alpha-tubulin deacetylation in mammalian cells. Tubacin does not affect the level of histone acetylation, gene-expression patterns, or cell-cycle progression. We provide evidence that class II histone deacetylase 6 (HDAC6) is the intracellular target of tubacin. Only one of the two catalytic domains of HDAC6 possesses tubulin deacetylase activity, and only this domain is bound by tubacin. Tubacin treatment did not affect the stability of microtubules but did decrease cell motility. HDAC6 overexpression disrupted the localization of p58, a protein that mediates binding of Golgi elements to microtubules. Our results highlight the role of alpha-tubulin acetylation in mediating the localization of microtubule-associated proteins. They also suggest that small molecules that selectively inhibit HDAC6-mediated alpha-tubulin deacetylation, a first example of which is tubacin, might have therapeutic applications as antimetastatic and antiangiogenic agents.

3T3 Cells↗

PubMed2003

Chemical genetic modifier screens: small molecule trichostatin suppressors as probes of intracellular histone and tubulin acetylation.

Histone deacetylase (HDAC) inhibitors are being developed as new clinical agents in cancer therapy, in part because they interrupt cell cycle progression in transformed cell lines. To examine cell cycle arrest induced by HDAC inhibitor trichostatin A (TSA), a cytoblot cell-based screen was used to identify small molecule suppressors of this process. TSA suppressors (ITSAs) counteract TSA-induced cell cycle arrest, histone acetylation, and transcriptional activation. Hydroxamic acid-based HDAC inhibitors like TSA and suberoylanilide hydroxamic acid (SAHA) promote acetylation of cytoplasmic alpha-tubulin as well as histones, a modification also suppressed by ITSAs. Although tubulin acetylation appears irrelevant to cell cycle progression and transcription, it may play a role in other cellular processes. Small molecule suppressors such as the ITSAs, available from chemical genetic suppressor screens, may prove to be valuable probes of many biological processes.

Acetylation↗

PubMed2003

Multidimensional chemical genetic analysis of diversity-oriented synthesis-derived deacetylase inhibitors using cell-based assays.

Systematic chemical genetics aims to explore the space representing interactions between small molecules and biological systems. Beyond measuring binding interactions and enzyme inhibition, measuring changes in the activity of proteins in intact signaling networks is necessary. Toward this end, we are partitioning chemical space into regions with different biological activities using a panel of cell-based assays and small molecule "chemical genetic modifiers." Herein, we report on the use of this methodology for the discovery of 617 small molecule inhibitors of histone deacetylases from a multidimensional screen of an encoded, diversity-oriented synthesis library. Following decoding of chemical tags and resynthesis, we demonstrate the selectivity of one inhibitory molecule (tubacin) toward alpha-tubulin deacetylation and another (histacin) toward histone deacetylation. These small molecules will facilitate dissecting the role of acetylation in a variety of cell biological processes.

Acetylation↗