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Cambridge, MA, United States

Byron S.A.,Translational Genomics Research Institute | Loch D.C.,Queensland University of Technology | Wellens C.L.,Translational Genomics Research Institute | Wortmann A.,Queensland University of Technology | And 5 more authors.
Molecular Cancer | Year: 2012

Background: Melanoma is the most lethal form of skin cancer, but recent advances in molecularly targeted agents against the Ras/Raf/MAPK pathway demonstrate promise as effective therapies. Despite these advances, resistance remains an issue, as illustrated recently by the clinical experience with vemurafenib. Such acquired resistance appears to be the result of parallel pathway activation, such as PI3K, to overcome single-agent inhibition. In this report, we describe the cytotoxicity and anti-tumour activity of the novel MEK inhibitor, E6201, in a broad panel of melanoma cell lines (n = 31) of known mutational profile in vitro and in vivo. We further test the effectiveness of combining E6201 with an inhibitor of PI3K (LY294002) in overcoming resistance in these cell lines.Results: The majority of melanoma cell lines were either sensitive (IC50 < 500 nM, 24/31) or hypersensitive (IC50 < 100 nM, 18/31) to E6201. This sensitivity correlated with wildtype PTEN and mutant BRAF status, whereas mutant RAS and PI3K pathway activation were associated with resistance. Although MEK inhibitors predominantly exert a cytostatic effect, E6201 elicited a potent cytocidal effect on most of the sensitive lines studied, as evidenced by Annexin positivity and cell death ELISA. Conversely, E6201 did not induce cell death in the two resistant melanoma cell lines tested. E6201 inhibited xenograft tumour growth in all four melanoma cell lines studied to varying degrees, but a more pronounced anti-tumour effect was observed for cell lines that previously demonstrated a cytocidal response in vitro. In vitro combination studies of E6201 and LY294002 showed synergism in all six melanoma cell lines tested, as defined by a mean combination index < 1.Conclusions: Our data demonstrate that E6201 elicits a predominantly cytocidal effect in vitro and in vivo in melanoma cells of diverse mutational background. Resistance to E6201 was associated with disruption of PTEN and activation of downstream PI3K signalling. In keeping with these data we demonstrate that co-inhibition of MAPK and PI3K is effective in overcoming resistance inherent in melanoma. © 2012 Byron et al.; licensee BioMed Central Ltd. Source

Chou D.H.-C.,The Broad Institute of MIT and Harvard | Duvall J.R.,The Broad Institute of MIT and Harvard | Gerard B.,The Broad Institute of MIT and Harvard | Liu H.,The Broad Institute of MIT and Harvard | And 7 more authors.
ACS Medicinal Chemistry Letters | Year: 2011

The synthesis of a stereochemically diverse library of medium-sized rings accessible via a "build/couple/pair" strategy is described. Key aspects of the synthesis include S NAr cycloetherification of a linear amine template to afford eight stereoisomeric eight-membered lactams and subsequent solid-phase diversification of these scaffolds to yield a 6488-membered library. Screening of this compound collection in a cell-based assay for the suppression of cytokine-induced β-cell apoptosis resulted in the identification of a small-molecule suppressor capable of restoring glucose-stimulated insulin secretion in a rat β-cell line. The presence of all stereoisomers in the screening collection enabled preliminary determination of the structural and stereochemical requirements for cellular activity, while efficient follow-up chemistry afforded BRD0476 (probe ML187), which had an approximately 3-fold increase in activity. These results demonstrate the utility of diversity-oriented synthesis to probe discovery using cell-based screening and the importance of including stereochemical diversity in screening collections for the development of stereo/structure-activity relationships. © 2011 American Chemical Society. Source

Ren W.,Tsinghua University | Bian Y.,Tsinghua University | Zhang Z.,Tsinghua University | Shang H.,Tsinghua University | And 6 more authors.
Angewandte Chemie - International Edition | Year: 2012

Let's swap: A scalable, atom-economic, enantio-, and diastereoselective synthetic route to trisubstituted γ-butyrolactones based on a Wagner-Meerwein-type dyotropic rearrangement of cis-β-lactones is described (see scheme). This methodology was applied in efficient and protecting-group-free formal syntheses and total syntheses of various xanthanolide natural products. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source

Zhang P.,Tsinghua University | Wang Y.,Tsinghua University | Bao R.,Tsinghua University | Luo T.,H3 Biomedicine Inc. | And 2 more authors.
Organic Letters | Year: 2012

Enantioselective total syntheses of katsumadain and katsumadain C were achieved concisely through a biomimetic approach. Assembly of styryl-2-pyranone (3) and monoterpene 6 via acid-promoted regio- and stereoselective C-C bond formation afforded katsumadain (2), which underwent the photoinduced [2 + 2] dimerization in a head-to-tail mode to furnish katsumadain C (1). © 2011 American Chemical Society. Source

Gerard B.,The Broad Institute of MIT and Harvard | Duvall J.R.,The Broad Institute of MIT and Harvard | Lowe J.T.,The Broad Institute of MIT and Harvard | Murillo T.,The Broad Institute of MIT and Harvard | And 4 more authors.
ACS Combinatorial Science | Year: 2011

We have implemented an aldol-based "build/couple/pair" (B/C/P) strategy for the synthesis of stereochemically diverse 8-membered lactam and sultam scaffolds via S NAr cycloetherification. Each scaffold contains two handles, an amine and aryl bromide, for solid-phase diversification via N-capping and Pd-mediated cross coupling. A sparse matrix design strategy that achieves the dual objective of controlling physicochemical properties and selecting diverse library members was implemented. The production of two 8000-membered libraries is discussed including a full analysis of library purity and property distribution. Library diversity was evaluated in comparison to the Molecular Library Small Molecule Repository (MLSMR) through the use of a multifusion similarity (MFS) map and principal component analysis (PCA). © 2011 American Chemical Society. Source

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