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Systematic discovery of multicomponent therapeutics
TLDR
Systematic combination screening may ultimately be useful for exploring the connectivity of biological pathways and, when performed with reference-listed drugs, may result in the discovery of new combination drug regimens.
Diversity-oriented synthesis yields novel multistage antimalarial inhibitors
TLDR
These findings identify bicyclic azetidines with the potential to both cure and prevent transmission of the disease as well as protect at-risk populations with a single oral dose, highlighting the strength of diversity-oriented synthesis in revealing promising therapeutic targets.
Stereoselective Synthesis of over Two Million Compounds Having Structural Features Both Reminiscent of Natural Products and Compatible with Miniaturized Cell-Based Assays
TLDR
The synthetic strategy undertaken is to develop highly efficient multistep syntheses of natural product-like compounds that include several coupling steps and to use split-pool techniques at these steps in order to generate diverse outcomes.
Macrocyclic Hedgehog Pathway Inhibitors: Optimization of Cellular Activity and Mode of Action Studies
TLDR
Studies with Patched knockout cells and competition studies with the Smoothened (Smo) agonists SAG and purmorphamine demonstrate that in contrast to robotnikinin, select analogues are Smo antagonists.
High-throughput identification of genotype-specific cancer vulnerabilities in mixtures of barcoded tumor cell lines
TLDR
A method called PRISM is reported that allows pooled screening of mixtures of cancer cell lines by labeling each cell line with 24-nucleotide barcodes and revealed the expected patterns of cell killing seen in conventional (unpooled) assays.
Chemical structure-guided design of dynapyrazoles, cell-permeable dynein inhibitors with a unique mode of action
TLDR
Dynapyrazoles are identified as inhibitors more potent than ciliobrevins of cytoplasmic dyneins, suggesting that chemical-structure-based analyses can lead to inhibitors with improved properties and distinct modes of inhibition.
Selective Phenylimidazole-based Inhibitors of the Mycobacterium tuberculosis Proteasome.
TLDR
Using a structure-guided and flow chemistry-enabled study of structure-activity relationships, phenylimidazole-based peptidomimetics that are highly potent for Mtb20S are developed that shed light on their selectivity for mycobacterial rather than human proteasomes.
Loss of immunoreactivity for human calmodulin-like protein is an early event in breast cancer development.
TLDR
Findings support the hypotheses that CLP behaves as a functional tumor suppressor protein and is downregulated early in breast cancer progression.
Modulators of Hepatic Lipoprotein Metabolism Identified in a Search for Small-Molecule Inducers of Tribbles Pseudokinase 1 Expression
TLDR
A high throughput phenotypic screen based on quantitative RT-PCR assay identified a series of benzofuran-based compounds that upregulate TRIB1 expression and phenocopy the effects of TRIB 1 cDNA overexpression, indicating that these compounds represent a novel class of chemically tractable small-molecule modulators that shift cellular lipoprotein metabolism in HepG2 cells from lipogenesis to scavenging.
Semisynthetic cyclopamine analogues as potent and orally bioavailable hedgehog pathway antagonists.
TLDR
The synthesis of a novel class of hedgehog antagonists derived from cyclopamine was homologated utilizing a sequence of chemoselective cyclopropanation and stereoselectives acid-catalyzed rearrangement.
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