16 research outputs found
Total Synthesis of the Unusual Marine Alkaloid (−)-Papuamine Utilizing a Novel Imino Ene Reaction J
.beta.-Tosylethylamine: A Useful Reagent for Preparation of N-Protected Amides, Carbamates, and Related Compounds. Application to Synthesis of .beta.-Lactams
Antroquinonol A: Scalable Synthesis and Preclinical Biology of a Phase 2 Drug Candidate
The
fungal-derived Taiwanese natural product antroquinonol A has attracted
both academic and commercial interest due to its reported exciting
biological properties. This reduced quinone is currently in phase
II trials (USA and Taiwan) for the treatment of non-small-cell lung
carcinoma (NSCLC) and was recently granted orphan drug status by the
FDA for the treatment of pancreatic cancer and acute myeloid leukemia.
Pending successful completion of human clinical trials, antroquinonol
is expected to be commercialized under the trade name Hocena. A synthesis-enabled
biological re-examination of this promising natural product, however,
reveals minimal <i>in vitro</i> and <i>in vivo</i> antitumor activity in preclinical
models
Discovery of Potent Heterodimeric Antagonists of Inhibitor of Apoptosis Proteins (IAPs) with Sustained Antitumor Activity
The
prominent role of IAPs in controlling cell death and their
overexpression in a variety of cancers has prompted the development
of IAP antagonists as potential antitumor therapies. We describe the
identification of a series of heterodimeric antagonists with highly
potent antiproliferative activities in cIAP- and XIAP-dependent cell
lines. Compounds <b>15</b> and <b>17</b> further demonstrate
curative efficacy in human melanoma and lung cancer xenograft models
and are promising candidates for advanced studies
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Receptor-Mediated Delivery of CRISPR-Cas9 Endonuclease for Cell-Type-Specific Gene Editing.
CRISPR-Cas RNA-guided endonucleases hold great promise for disrupting or correcting genomic sequences through site-specific DNA cleavage and repair. However, the lack of methods for cell- and tissue-selective delivery currently limits both research and clinical uses of these enzymes. We report the design and in vitro evaluation of S. pyogenes Cas9 proteins harboring asialoglycoprotein receptor ligands (ASGPrL). In particular, we demonstrate that the resulting ribonucleoproteins (Cas9-ASGPrL RNP) can be engineered to be preferentially internalized into cells expressing the corresponding receptor on their surface. Uptake of such fluorescently labeled proteins in liver-derived cell lines HEPG2 (ASGPr+) and SKHEP (control; diminished ASGPr) was studied by live cell imaging and demonstrates increased accumulation of Cas9-ASGPrL RNP in HEPG2 cells as a result of effective ASGPr-mediated endocytosis. When uptake occurred in the presence of a peptide with endosomolytic properties, we observed receptor-facilitated and cell-type specific gene editing that did not rely on electroporation or the use of transfection reagents. Overall, these in vitro results validate the receptor-mediated delivery of genome-editing enzymes as an approach for cell-selective gene editing and provide a framework for future potential applications to hepatoselective gene editing in vivo
Discovery of Potent Heterodimeric Antagonists of Inhibitor of Apoptosis Proteins (IAPs) with Sustained Antitumor Activity
The
prominent role of IAPs in controlling cell death and their
overexpression in a variety of cancers has prompted the development
of IAP antagonists as potential antitumor therapies. We describe the
identification of a series of heterodimeric antagonists with highly
potent antiproliferative activities in cIAP- and XIAP-dependent cell
lines. Compounds <b>15</b> and <b>17</b> further demonstrate
curative efficacy in human melanoma and lung cancer xenograft models
and are promising candidates for advanced studies