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A cell-based screen identifies ATR inhibitors with synthetic lethal properties for cancer-associated mutations
A cell-based screening strategy is described that has allowed us to identify compounds with ATR inhibitory activity in the nanomolar range that are being tested for cancer chemotherapy and are also very potent against ATM, ATR and the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs). Expand
Tissue damage and senescence provide critical signals for cellular reprogramming in vivo
It is found that the expression of OSKM in vivo not only triggers reprogramming of some cells but also inflicts extensive damage on many other cells, driving them into a state known as cellular senescence. Expand
Pten positively regulates brown adipose function, energy expenditure, and longevity.
A role of Pten is uncovered in promoting energy expenditure, thus decreasing nutrient storage and its associated damage, and a synthetic PI3K inhibitor also increases energy expenditure and hyperactivates the BAT in mice. Expand
Alternative Activation Mechanisms of Protein Kinase B Trigger Distinct Downstream Signaling Responses*
It is shown that PKB activity in cells can be triggered independently of PI3K by initial hydrophobic motif phosphorylation, presumably through a mechanism analogous to other AGC kinases, and different modes of PKB activation result inosphorylation of distinct downstream targets. Expand
Therapeutic inhibition of TRF1 impairs the growth of p53-deficient K-RasG12V-induced lung cancer by induction of telomeric DNA damage
Induction of acute telomere uncapping emerges as a potential new therapeutic target for lung cancer by inhibition of TRF1 shelterin protein by blocking the growth of already established lung carcinomas without affecting mouse survival or tissue function. Expand
Crossing the Valley of Death in Drug Discovery
A General and Highly Efficient Solid Phase Synthesis of Oligosaccharides. Total Synthesis of a Heptasaccharide Phytoalexin Elicitor (HPE)
A new solid phase method for the synthesis of complex oligosaccharides is described. The method involves attachment to phenolic polystyrene of the first carbohydrate unit, through its anomericExpand
Designed Epothilones: Combinatorial Synthesis, Tubulin Assembly Properties, abd Cytotoxic Action against Taxol-Resistant Tumor Cells†
A library of epothilone A and B analogues, which was constructed by solid-phase combinatorial synthesis using SMART Microreactors and solution chemistry, was screened in two different tubulin bindingExpand
A novel phosphatidylinositol 3-kinase (PI3K) inhibitor directs a potent FOXO-dependent, p53-independent cell cycle arrest phenotype characterized by the differential induction of a subset of
The results presented here highlight that PI3K inhibition activates specific FOXO-dependent genes that mediate cell cycle arrest in breast cancer cells and thus the exclusion of FOXO transcription factors from the nucleus is a key feature of breast cancer. Expand
Modulation of telomere protection by the PI3K/AKT pathway
It is demonstrated that PI3K, via downstream targets, regulates TRF1 via phosphorylation, an essential component of the shelterin complex, and PI3k and AKT as novel targets for chemical modulation of telomere protection. Expand