Publications (11) View all
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Article: The development of a high-content screening binding assay for the smoothened receptor.
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ABSTRACT: In this study, the development of an image-based high-content screening (HCS) binding assay for the seven-transmembrane (7TM) receptor Smoothened (Smo) is described. Using BacMam-based gene delivery of Smo, BODIPY-cyclopamine as a fluorescent probe, and a confocal imaging system, a robust 384-well assay that could be used for high-throughput compound profiling activities was developed. The statistically robust HCS binding assay was developed through optimization of multiple parameters, including cell transduction conditions, Smo expression levels, the image analysis algorithm, and staining procedures. Evaluation of structurally diverse compounds, including functional Smo activators, inhibitors, and related analogs, demonstrated good compound potency correlations between high-content imaging binding, membrane fluorescence polarization binding, and gene reporter assays. Statistical analysis of data from a screening test set of compounds at a single 10-µM concentration suggested that the high-content imaging Smo binding assay is amenable for use in hit identification. The 384-well HCS assay was rapidly developed and met statistical assay performance targets, thus demonstrating its utility as a fluorescent whole-cell binding assay suitable for compound screening and profiling.Journal of Biomolecular Screening 05/2012; 17(7):900-11. · 2.05 Impact Factor -
Article: Development of potent B-RafV600E inhibitors containing an arylsulfonamide headgroup.
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ABSTRACT: A potent series of inhibitors against the B-Raf(V600E) kinase have been developed that show excellent activity in cellular assays and good oral bioavailability in rats. The key structural features of the series are an arylsulfonamide headgroup, a thiazole core, and a fluorine ortho to the sulfonamide nitrogen.Bioorganic & medicinal chemistry letters 08/2011; 21(15):4436-40. · 2.65 Impact Factor -
Article: Design of potent thiophene inhibitors of polo-like kinase 1 with improved solubility and reduced protein binding.
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ABSTRACT: A series of thiophene PLK1 inhibitors was optimized for increased solubility and reduced protein binding through the appendage of basic amine functionality. Interesting selectivity between PLK1 and PLK3 was also obtained through these modifications.Bioorganic & medicinal chemistry letters 02/2009; 19(6):1694-7. · 2.65 Impact Factor -
Article: Yb(OTf)(3)-Catalyzed oxymercuration of homoallylic alcohol-derived hemiacetals and hemiketals.
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ABSTRACT: 1,3-Diol synthons, protected as acetonides or benzylidene acetals, may be synthesized efficiently from homoallylic alcohols and acetone or benzaldehyde by oxymercuration of the derived hemiketals and hemiacetals with HgClOAc. The use of catalytic amounts of Yb(OTf)(3) is crucial to the success of the reaction, which was determined to be reversible.Organic Letters 11/2000; 2(20):3197-9. · 5.86 Impact Factor -
Article: Room-temperature Pd-catalyzed amidation of aryl bromides using tert-butyl carbamate.
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ABSTRACT: The scope of Pd-catalyzed synthesis of N-Boc-protected anilines from aryl bromides and commercially available tert-butyl carbamate is described. For the first time, this process can be conducted at room temperature (17-22 degrees C) using a combination of Pd(2)dba(3).CHCl(3) and a monodentate ligand, tert-butyl X-Phos. Use of sodium tert-butoxide is crucial to the success of the reaction, which proceeds in 43-83% yield.The Journal of Organic Chemistry 07/2009; 74(12):4634-7. · 4.45 Impact Factor
