@article {686013,
	title = {Colchicine acts selectively in the liver to induce hepatokines that inhibit myeloid cell activation},
	journal = {Nat Metab},
	volume = {3},
	number = {4},
	year = {2021},
	month = {2021 04},
	pages = {513-522},
	abstract = {Colchicine has served as a traditional medicine for millennia and remains widely used to treat inflammatory and other disorders. Colchicine binds tubulin and depolymerizes microtubules, but it remains unclear how this mechanism blocks myeloid cell recruitment to inflamed tissues. Here we show that colchicine inhibits myeloid cell activation via an indirect mechanism involving the release of hepatokines. We find that a safe dose of colchicine depolymerizes microtubules selectively in hepatocytes but not in circulating myeloid cells. Mechanistically, colchicine triggers Nrf2 activation in hepatocytes, leading to secretion of anti-inflammatory hepatokines, including growth differentiation factor 15 (GDF15). Nrf2 and GDF15 are required for the anti-inflammatory action of colchicine in vivo. Plasma from colchicine-treated mice inhibits inflammatory signalling in myeloid cells in a GDF15-dependent manner, by positive regulation of SHP-1 (PTPN6) phosphatase, although the precise molecular identities of colchicine-induced GDF15 and its receptor require further characterization. Our work shows that the efficacy and safety of colchicine depend on its selective action on hepatocytes, and reveals a new axis of liver-myeloid cell communication. Plasma GDF15 levels and myeloid cell SHP-1 activity may be useful pharmacodynamic biomarkers of colchicine action.},
	keywords = {Animals, Anti-Inflammatory Agents, Non-Steroidal, Antioxidants, Colchicine, Computer Simulation, Cytokines, Growth Differentiation Factor 15, Hepatocytes, Humans, Liver, Mice, Mice, Inbred C57BL, Microtubules, Myeloid Cells, NF-E2-Related Factor 2, Peritonitis, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Signal Transduction},
	issn = {2522-5812},
	doi = {10.1038/s42255-021-00366-y},
	author = {Weng, Jui-Hsia and Koch, Peter David and Luan, Harding H and Tu, Ho-Chou and Shimada, Kenichi and Ngan, Iris and Ventura, Richard and Jiang, Ruomu and Mitchison, Timothy J}
}
@article {686014,
	title = {shinyDepMap, a tool to identify targetable cancer genes and their functional connections from Cancer Dependency Map data},
	journal = {Elife},
	volume = {10},
	year = {2021},
	month = {2021 Feb 08},
	abstract = {Individual cancers rely on distinct essential genes for their survival. The Cancer Dependency Map (DepMap) is an ongoing project to uncover these gene dependencies in hundreds of cancer cell lines. To make this drug discovery resource more accessible to the scientific community, we built an easy-to-use browser, shinyDepMap (https://labsyspharm.shinyapps.io/depmap). shinyDepMap combines CRISPR and shRNA data to determine, for each gene, the growth reduction caused by knockout/knockdown and the selectivity of this effect across cell lines. The tool also clusters genes with similar dependencies, revealing functional relationships. shinyDepMap can be used to (1) predict the efficacy and selectivity of drugs targeting particular genes; (2) identify maximally sensitive cell lines for testing a drug; (3) target hop, that is, navigate from an undruggable protein with the desired selectivity profile, such as an activated oncogene, to more druggable targets with a similar profile; and (4) identify novel pathways driving cancer cell growth and survival.},
	issn = {2050-084X},
	doi = {10.7554/eLife.57116},
	author = {Shimada, Kenichi and Bachman, John A and Muhlich, Jeremy L. and Mitchison, Timothy J}
}
@article {686015,
	title = {Mesenchymal subtype neuroblastomas are addicted to TGF-βR2/HMGCR-driven protein geranylgeranylation},
	journal = {Sci Rep},
	volume = {10},
	number = {1},
	year = {2020},
	month = {2020 07 01},
	pages = {10748},
	abstract = {The identification of targeted agents with high therapeutic index is a major challenge for cancer drug discovery. We found that screening chemical libraries across neuroblastoma (NBL) tumor subtypes for selectively-lethal compounds revealed metabolic dependencies that defined each subtype. Bioactive compounds were screened across cell models of mesenchymal (MESN) and MYCN-amplified (MYCNA) NBL subtypes, which revealed the mevalonate and folate biosynthetic pathways as MESN-selective dependencies. Treatment with lovastatin, a mevalonate biosynthesis inhibitor, selectively inhibited protein prenylation and induced apoptosis in MESN cells, while having little effect in MYCNA lines. Statin sensitivity was driven by HMGCR expression, the rate-limiting enzyme for cholesterol synthesis, which correlated with statin sensitivity across NBL cell lines, thus providing a drug sensitivity biomarker. Comparing expression profiles from sensitive and resistant cell lines revealed a TGFBR2 signaling axis that regulates HMGCR, defining an actionable addiction in that leads to MESN-subtype-dependent apoptotic cell death.},
	keywords = {Antineoplastic Agents, Apoptosis, Biomarkers, Tumor, Cell Line, Tumor, Fluvastatin, Humans, Hydroxymethylglutaryl CoA Reductases, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Lipids, Lovastatin, Methotrexate, N-Myc Proto-Oncogene Protein, Neuroblastoma, Protein Prenylation, Receptor, Transforming Growth Factor-beta Type II, RNA, Small Interfering, Signal Transduction, Triamterene},
	issn = {2045-2322},
	doi = {10.1038/s41598-020-67310-0},
	author = {Stokes, Michael E and Small, Jonnell Candice and Vasciaveo, Alessandro and Shimada, Kenichi and Hirschhorn, Tal and Califano, Andrea and Stockwell, Brent R.}
}
@article {Shimada2019.12.13.874776,
	title = {A tool for browsing the Cancer Dependency Map reveals functional connections between genes and helps predict the efficacy and selectivity of candidate cancer drugs},
	journal = {bioRxiv},
	year = {2019},
	publisher = {Cold Spring Harbor Laboratory},
	abstract = {Individual cancers rely on distinct essential genes for their survival. The Cancer Dependency Map (DepMap) is an ongoing project to uncover gene dependency in hundreds of cancer cell lines. DepMap is a powerful drug discovery tool, but can be challenging to use without professional bioinformatics assistance. We combined CRISPR and shRNA screening data from DepMap and built a non-programmer-friendly browser (https://labsyspharm.shinyapps.io/depmap) that reports, for each gene, the growth reduction that can be expected on the loss of a gene or inhibition of its action (efficacy) and the selectivity of this effect across cell lines. Cluster analysis revealed proteins that work together in pathways or complexes. This tool can be used to 1) predict the efficacy and selectivity of candidate drugs; 2) identify targets for highly selective drugs; 3) identify maximally sensitive cell lines for testing a drug; 4) target hop, i.e., navigate from an undruggable protein with the desired selectively profile, such as an activated oncogene, to more druggable targets with a similar profile; and 5) identify novel pathways needed for cancer cell growth and survival.},
	doi = {10.1101/2019.12.13.874776},
	url = {https://www.biorxiv.org/content/early/2019/12/18/2019.12.13.874776},
	author = {Shimada, Kenichi and Muchlich, Jeremy L and Mitchison, Timothy J}
}
@article {643729,
	title = {Human Pluripotency Is Initiated and Preserved by a Unique Subset of Founder Cells},
	journal = {Cell},
	volume = {177},
	number = {4},
	year = {2019},
	month = {2019 May 02},
	pages = {910-924.e22},
	abstract = {The assembly of organized colonies is the earliest manifestation in the derivation or induction of pluripotency in~vitro. However, the necessity and origin of this assemblance is unknown. Here, we identify human pluripotent founder cells (hPFCs) that initiate, as well as preserve and establish, pluripotent stem cell (PSC) cultures. PFCs are marked by N-cadherin expression (NCAD) and reside exclusively at the colony boundary of primate PSCs. As demonstrated by functional analysis, hPFCs harbor the clonogenic capacity of PSC cultures and emerge prior to commitment events or phenotypes associated with pluripotent reprogramming. Comparative single-cell analysis with pre- and post-implantation primate embryos revealed hPFCs share hallmark properties with primitive endoderm (PrE) and can be regulated by non-canonical Wnt signaling. Uniquely informed by primate embryo organization in~vivo, our study defines a subset of founder cells critical to the establishment pluripotent state.},
	issn = {1097-4172},
	doi = {10.1016/j.cell.2019.03.013},
	author = {Nakanishi, Mio and Mitchell, Ryan R and Benoit, Yannick D and Orlando, Luca and Reid, Jennifer C and Shimada, Kenichi and Davidson, Kathryn C and Shapovalova, Zoya and Collins, Tony J and Nagy, Andras and Bhatia, Mickie}
}
@article {632388,
	title = {Unsupervised identification of disease states from high-dimensional physiological and histopathological profiles},
	journal = {Mol Syst Biol},
	volume = {15},
	number = {2},
	year = {2019},
	month = {2019 Feb 19},
	pages = {e8636},
	abstract = {The liver and kidney in mammals play central roles in protecting the organism from xenobiotics and are at high risk of xenobiotic-induced injury. Xenobiotic-induced tissue injury has been extensively studied from both classical histopathological and biochemical perspectives. Here, we introduce a machine-learning approach to analyze toxicological response. Unsupervised characterization of physiological and histological changes in a large toxicogenomic dataset revealed nine discrete toxin-induced disease states, some of which correspond to known pathology, but others were novel. Analysis of dynamics revealed transitions between disease states at constant toxin exposure, mostly toward decreased pathology, implying induction of tolerance. Tolerance correlated with induction of known xenobiotic defense genes and decrease of novel ferroptosis sensitivity biomarkers, suggesting ferroptosis as a druggable driver of tissue pathophysiology. Lastly, mechanism of body weight decrease, a known primary marker for xenobiotic toxicity, was investigated. Combined analysis of food consumption, body weight, and molecular biomarkers indicated that organ injury promotes cachexia by whole-body signaling through Gdf15 and Igf1, suggesting strategies for therapeutic intervention that may be broadly relevant to human disease.},
	issn = {1744-4292},
	doi = {10.15252/msb.20188636},
	author = {Shimada, Kenichi and Mitchison, Timothy J}
}
@article {618391,
	title = {Copper-Binding Small Molecule Induces Oxidative Stress and Cell-Cycle Arrest in Glioblastoma-Patient-Derived Cells},
	journal = {Cell Chem Biol},
	volume = {25},
	number = {5},
	year = {2018},
	month = {2018 May 17},
	pages = {585-594.e7},
	abstract = {Transition metals are essential, but deregulation of their metabolism causes toxicity. Here, we report that the compound NSC319726 binds copper to induce oxidative stress and arrest glioblastoma-patient-derived cells at picomolar concentrations. Pharmacogenomic analysis suggested that NSC319726 and 65 other structural analogs exhibit lethality through metal binding. Although NSC319726 has been reported to function as a zinc ionophore, we~report here that this compound binds to copper~to~arrest cell growth. We generated and validated pharmacogenomic predictions: copper toxicity was substantially inhibited by hypoxia, through an hypoxia-inducible-factor-1α-dependent pathway; copper-bound NSC319726 induced the generation of reactive oxygen species and depletion of deoxyribosyl purines, resulting in cell-cycle arrest. These results suggest that metal-induced DNA damage may be a consequence of exposure to some xenobiotics, therapeutic agents, as well as other causes of copper dysregulation, and reveal a potent mechanism for targeting glioblastomas.},
	issn = {2451-9448},
	doi = {10.1016/j.chembiol.2018.02.010},
	author = {Shimada, Kenichi and Reznik, Eduard and Stokes, Michael E and Krishnamoorthy, Lakshmi and Bos, Pieter H and Song, Yuyu and Quartararo, Christine E and Pagano, Nen C and Carpizo, Darren R and deCarvalho, Ana C and Lo, Donald C and Stockwell, Brent R.}
}
@article {618392,
	title = {Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway},
	journal = {Nature},
	volume = {547},
	number = {7664},
	year = {2017},
	month = {2017 07 27},
	pages = {453-457},
	abstract = {Plasticity of the cell state has been proposed to drive resistance to multiple classes of cancer therapies, thereby limiting their effectiveness. A high-mesenchymal cell state observed in human tumours and cancer cell lines has been associated with resistance to multiple treatment modalities across diverse cancer lineages, but the mechanistic underpinning for this state has remained incompletely understood. Here we molecularly characterize this therapy-resistant high-mesenchymal cell state in human cancer cell lines and organoids and show that it depends on a druggable lipid-peroxidase pathway that protects against ferroptosis, a non-apoptotic form of cell death induced by the build-up of toxic lipid peroxides. We show that this cell state is characterized by activity of enzymes that promote the synthesis of polyunsaturated lipids. These lipids are the substrates for lipid peroxidation by lipoxygenase enzymes. This lipid metabolism creates a dependency on pathways converging on the phospholipid glutathione peroxidase (GPX4), a selenocysteine-containing enzyme that dissipates lipid peroxides and thereby prevents the iron-mediated reactions of peroxides that induce ferroptotic cell death. Dependency on GPX4 was found to exist across diverse therapy-resistant states characterized by high expression of ZEB1, including epithelial-mesenchymal transition in epithelial-derived carcinomas, TGFβ-mediated therapy-resistance in melanoma, treatment-induced neuroendocrine transdifferentiation in prostate cancer, and sarcomas, which are fixed in a mesenchymal state owing to their cells of origin. We identify vulnerability to ferroptic cell death induced by inhibition of a lipid peroxidase pathway as a feature of therapy-resistant cancer cells across diverse mesenchymal cell-state contexts.},
	keywords = {Cadherins, Cell Death, Cell Line, Tumor, Cell Lineage, Cell Transdifferentiation, Drug Resistance, Neoplasm, Epithelial-Mesenchymal Transition, Glutathione Peroxidase, Humans, Iron, Lipid Peroxidation, Lipid Peroxides, Male, Melanoma, Mesoderm, Neoplasms, Prostatic Neoplasms, Proteomics, Proto-Oncogene Proteins B-raf, Reproducibility of Results, Zinc Finger E-box-Binding Homeobox 1},
	issn = {1476-4687},
	doi = {10.1038/nature23007},
	author = {Viswanathan, Vasanthi S and Ryan, Matthew J and Dhruv, Harshil D and Gill, Shubhroz and Eichhoff, Ossia M and Seashore-Ludlow, Brinton and Kaffenberger, Samuel D and Eaton, John K and Shimada, Kenichi and Aguirre, Andrew J and Viswanathan, Srinivas R and Chattopadhyay, Shrikanta and Tamayo, Pablo and Yang, Wan Seok and Rees, Matthew G and Chen, Sixun and Boskovic, Zarko V. and Javaid, Sarah and Huang, Cherrie and Wu, Xiaoyun and Tseng, Yuen-Yi and Roider, Elisabeth M and Gao, Dong and Cleary, James M and Wolpin, Brian M and Mesirov, Jill P and Haber, Daniel A. and Engelman, Jeffrey A and Boehm, Jesse S. and Kotz, Joanne D and Hon, Cindy S and Chen, Yu and Hahn, William C. and Levesque, Mitchell P and Doench, John G and Berens, Michael E and Shamji, Alykhan F. and Clemons, Paul A. and Stockwell, Brent R. and Schreiber, Stuart L.}
}
@article {472931,
	title = {Cell-Line Selectivity Improves the Predictive Power of Pharmacogenomic Analyses and Helps Identify NADPH as Biomarker for Ferroptosis Sensitivity.},
	journal = {Cell Chem Biol},
	volume = {23},
	number = {2},
	year = {2016},
	month = {2016 Feb 18},
	pages = {225-35},
	abstract = {Precision medicine in oncology requires not only identification of cancer-associated mutations but also effective drugs for each cancer genotype, which is still a largely unsolved problem. One approach for the latter challenge has been large-scale testing of small molecules in genetically characterized cell lines. We hypothesized that compounds with high cell-line-selective lethality exhibited consistent results across such pharmacogenomic studies. We analyzed the compound sensitivity data of 6,259 lethal compounds from the NCI-60 project. A total of 2,565 cell-line-selective lethal compounds were identified and grouped into 18 clusters based on their median growth inhibitory GI50 profiles across the 60 cell lines, which were shown to represent distinct mechanisms of action. Further transcriptome analysis revealed a biomarker, NADPH abundance, for predicting sensitivity to ferroptosis-inducing compounds, which we experimentally validated. In summary, incorporating cell-line-selectivity filters improves the predictive power of pharmacogenomic analyses and enables discovery of biomarkers that predict the sensitivity of cells to specific cell death inducers.},
	issn = {2451-9456},
	doi = {10.1016/j.chembiol.2015.11.016},
	author = {Shimada, Kenichi and Hayano, Miki and Pagano, Nen C and Stockwell, Brent R.}
}
@article {472926,
	title = {tRNA synthase suppression activates de novo cysteine synthesis to compensate for cystine and glutathione deprivation during ferroptosis.},
	journal = {Mol Cell Oncol},
	volume = {3},
	number = {2},
	year = {2016},
	month = {2016 Mar},
	pages = {e1091059},
	abstract = {Glutathione is a major endogenous reducing agent in cells, and cysteine is a limiting factor in glutathione synthesis. Cysteine is obtained by uptake or biosynthesis, and mammalian cells often rely on either one or the other pathway. Because of the scarcity of glutathione, blockade of cysteine uptake causes oxidative cell death known as ferroptosis. A new study suggests that tRNA synthetase suppression activates the endogenous biosynthesis of cysteine, compensates such cysteine loss, and thus makes cells resistant to ferroptosis.},
	doi = {10.1080/23723556.2015.1091059},
	author = {Shimada, Kenichi and Stockwell, Brent R.}
}
@article {472921,
	title = {Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis.},
	journal = {Nat Chem Biol},
	volume = {12},
	number = {7},
	year = {2016},
	month = {2016 Jul},
	pages = {497-503},
	abstract = {Apoptosis is one type of programmed cell death. Increasingly, non-apoptotic cell death is recognized as being genetically controlled, or {\textquoteright}regulated{\textquoteright}. However, the full extent and diversity of alternative cell death mechanisms remain uncharted. Here we surveyed the landscape of pharmacologically accessible cell death mechanisms. In an examination of 56 caspase-independent lethal compounds, modulatory profiling showed that 10 compounds induced three different types of regulated non-apoptotic cell death. Optimization of one of those ten resulted in the discovery of FIN56, a specific inducer of ferroptosis. Ferroptosis has been found to occur when the lipid-repair enzyme GPX4 is inhibited. FIN56 promoted degradation of GPX4. FIN56 also bound to and activated squalene synthase, an enzyme involved in isoprenoid biosynthesis, independent of GPX4 degradation. These discoveries show that dysregulation of lipid metabolism is associated with ferroptosis. This systematic approach is a means to discover and characterize novel cell death phenotypes.},
	issn = {1552-4450},
	doi = {10.1038/nchembio.2079},
	author = {Shimada, Kenichi and Skouta, Rachid and Kaplan, Anna and Yang, Wan Seok and Hayano, Miki and Dixon, Scott J and Brown, Lewis M and Valenzuela, Carlos A and Wolpaw, Adam J and Stockwell, Brent R.}
}
@article {472941,
	title = {Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models.},
	journal = {J Am Chem Soc},
	volume = {136},
	number = {12},
	year = {2014},
	month = {2014 Mar 26},
	pages = {4551-6},
	abstract = {Ferrostatin-1 (Fer-1) inhibits ferroptosis, a form of regulated, oxidative, nonapoptotic cell death. We found that Fer-1 inhibited cell death in cellular models of Huntington{\textquoteright}s disease (HD), periventricular leukomalacia (PVL), and kidney dysfunction; Fer-1 inhibited lipid peroxidation, but not mitochondrial reactive oxygen species formation or lysosomal membrane permeability. We developed a mechanistic model to explain the activity of Fer-1, which guided the development of ferrostatins with improved properties. These studies suggest numerous therapeutic uses for ferrostatins, and that lipid peroxidation mediates diverse disease phenotypes.},
	keywords = {Cell Death, Cyclohexylamines, Huntington Disease, Kidney Diseases, Leukomalacia, Periventricular, Lipid Peroxidation, Membrane Lipids, Oxidation-Reduction, Phenylenediamines},
	issn = {1520-5126},
	doi = {10.1021/ja411006a},
	author = {Skouta, Rachid and Dixon, Scott J and Wang, Jianlin and Dunn, Denise E and Orman, Marina and Shimada, Kenichi and Rosenberg, Paul A and Lo, Donald C and Weinberg, Joel M and Linkermann, Andreas and Stockwell, Brent R.}
}
@article {472946,
	title = {Regulation of ferroptotic cancer cell death by GPX4.},
	journal = {Cell},
	volume = {156},
	number = {1-2},
	year = {2014},
	month = {2014 Jan 16},
	pages = {317-31},
	abstract = {Ferroptosis is a form of nonapoptotic cell death for which key regulators remain unknown. We sought a common mediator for the lethality of 12 ferroptosis-inducing small molecules. We used targeted metabolomic profiling to discover that depletion of glutathione causes inactivation of glutathione peroxidases (GPXs) in response to one class of compounds and a chemoproteomics strategy to discover that GPX4 is directly inhibited by a second class of compounds. GPX4 overexpression and knockdown modulated the lethality of 12 ferroptosis inducers, but not of 11 compounds with other lethal mechanisms. In addition, two representative ferroptosis inducers prevented tumor growth in xenograft mouse tumor models. Sensitivity profiling in 177 cancer cell lines revealed that diffuse large B cell lymphomas and renal cell carcinomas are particularly susceptible to GPX4-regulated ferroptosis. Thus, GPX4 is an essential regulator of ferroptotic cancer cell death.},
	keywords = {Animals, Carbolines, Carcinoma, Renal Cell, Cell Death, Cell Line, Tumor, Gene Knockdown Techniques, Glutathione, Glutathione Peroxidase, Heterografts, Humans, Lymphoma, B-Cell, Mice, Neoplasm Transplantation, Neoplasms, Piperazines},
	issn = {1097-4172},
	doi = {10.1016/j.cell.2013.12.010},
	author = {Yang, Wan Seok and SriRamaratnam, Rohitha and Welsch, Matthew E and Shimada, Kenichi and Skouta, Rachid and Viswanathan, Vasanthi S and Cheah, Jaime H and Clemons, Paul A. and Shamji, Alykhan F. and Clish, Clary B and Brown, Lewis M and Girotti, Albert W and Cornish, Virginia W and Schreiber, Stuart L. and Stockwell, Brent R.}
}
@article {472936,
	title = {Unraveling the mechanism of cell death induced by chemical fibrils.},
	journal = {Nat Chem Biol},
	volume = {10},
	number = {11},
	year = {2014},
	month = {2014 Nov},
	pages = {969-76},
	abstract = {We previously discovered a small-molecule inducer of cell death, named 1541, that noncovalently self-assembles into chemical fibrils ({\textquoteright}chemi-fibrils{\textquoteright}) and activates procaspase-3 in vitro. We report here that 1541-induced cell death is caused by the fibrillar rather than the soluble form of the drug. A short hairpin RNA screen reveals that knockdown of genes involved in endocytosis, vesicle trafficking and lysosomal acidification causes partial 1541 resistance. We confirm the role of these pathways using pharmacological inhibitors. Microscopy shows that the fluorescent chemi-fibrils accumulate in punctae inside cells that partially colocalize with lysosomes. Notably, the chemi-fibrils bind and induce liposome leakage in vitro, suggesting they may do the same in cells. The chemi-fibrils induce extensive proteolysis including caspase substrates, yet modulatory profiling reveals that chemi-fibrils form a distinct class from existing inducers of cell death. The chemi-fibrils share similarities with proteinaceous fibrils and may provide insight into their mechanism of cellular toxicity.},
	keywords = {Amino Acid Sequence, Benzamides, Caspase 3, Cell Death, Cell proliferation, Coumarins, Dose-Response Relationship, Drug, Humans, K562 Cells, Lysosomes, Models, Biological, Molecular structure, Structure-Activity Relationship, Tumor Cells, Cultured},
	issn = {1552-4469},
	doi = {10.1038/nchembio.1639},
	author = {Julien, Olivier and Kampmann, Martin and Bassik, Michael C and Zorn, Julie A and Venditto, Vincent J and Shimbo, Kazutaka and Agard, Nicholas J and Shimada, Kenichi and Rheingold, Arnold L and Stockwell, Brent R. and Weissman, Jonathan S. and Wells, James A}
}
@article {472951,
	title = {Design and synthesis of Pictet-Spengler condensation products that exhibit oncogenic-RAS synthetic lethality and induce non-apoptotic cell death.},
	journal = {Bioorg Med Chem Lett},
	volume = {22},
	number = {17},
	year = {2012},
	month = {2012 Sep 1},
	pages = {5707-13},
	abstract = {A series of Pictet-Spengler condensation derivatives (tetrahydro-β-carbolines) was designed, synthesized and evaluated for lethality against a panel of seven cancer cell lines. Seven compounds (2a, 13, 20, 21, 27, 29 and 34) showed lethality in at least five cell lines. Among these, compound 27 showed a unique selectivity towards oncogenic-RAS expressing BJ-TERT/LT/ST/RAS(V12) tumor cells, compared to non-transformed BJ-TERT cells. Further investigation revealed that 27 induces cell death without activation of caspases. This represents a useful new probe of non-apoptotic cell death and oncogenic-RAS synthetic lethality.},
	keywords = {Antineoplastic Agents, Carbolines, Cell Death, Cell Line, Tumor, Cell Survival, Drug Design, Gene Expression Regulation, Neoplastic, Genes, ras, Humans, Neoplasms},
	issn = {1464-3405},
	doi = {10.1016/j.bmcl.2012.06.077},
	author = {Skouta, Rachid and Hayano, Miki and Shimada, Kenichi and Stockwell, Brent R.}
}
@article {472961,
	title = {Development of small-molecule probes that selectively kill cells induced to express mutant RAS.},
	journal = {Bioorg Med Chem Lett},
	volume = {22},
	number = {4},
	year = {2012},
	month = {2012 Feb 15},
	pages = {1822-6},
	abstract = {Synthetic lethal screening is a chemical biology approach to identify small molecules that selectively kill oncogene-expressing cell lines with the goal of identifying pathways that provide specific targets against cancer cells. We performed a high-throughput screen of 303,282 compounds from the National Institutes of Health-Molecular Libraries Small Molecule Repository (NIH-MLSMR) against immortalized BJ fibroblasts expressing HRAS(G12V) followed by a counterscreen of lethal compounds in a series of isogenic cells lacking the HRAS(G12V) oncogene. This effort led to the identification of two novel molecular probes (PubChem CID 3689413, ML162 and CID 49766530, ML210) with nanomolar potencies and 4-23-fold selectivities, which can potentially be used for identifying oncogene-specific pathways and targets in cancer cells.},
	keywords = {Animals, Apoptosis, Cell Line, Cell Line, Tumor, Drug Screening Assays, Antitumor, Fibroblasts, Humans, Inhibitory Concentration 50, Molecular structure, Mutation, Proto-Oncogene Proteins p21(ras), Rats, Small Molecule Libraries, Structure-Activity Relationship, Thiophenes},
	issn = {1464-3405},
	doi = {10.1016/j.bmcl.2011.09.047},
	author = {We{\"\i}wer, Michel and Bittker, Joshua A. and Lewis, Timothy A. and Shimada, Kenichi and Yang, Wan Seok and MacPherson, Lawrence and Dandapani, Sivaraman and Palmer, Michelle and Stockwell, Brent R. and Schreiber, Stuart L. and Munoz, Benito}
}
@article {472966,
	title = {Identification of Simple Compounds with Microtubule-Binding Activity That Inhibit Cancer Cell Growth with High Potency.},
	journal = {ACS Med Chem Lett},
	volume = {3},
	number = {1},
	year = {2012},
	month = {2012 Jan 12},
	pages = {35-38},
	abstract = {We analyzed more than 1 million small molecules with the goal of finding simple synthetic compounds that potently inhibit cancer cell growth. We identified three such compounds with unknown mechanisms of action. Subsequent studies revealed that all three of these small molecules target microtubules. These three scaffolds can serve as templates for developing new microtubule-targeted agents, overcoming the limits of existing microtubule-inhibiting drugs derived from complex natural products.},
	doi = {10.1021/ml200195s},
	author = {Yang, Wan Seok and Shimada, Kenichi and Delva, Darnelle and Patel, Milesh and Ode, Egberamwen and Skouta, Rachid and Stockwell, Brent R.}
}
@article {472956,
	title = {Discovery of Mdm2-MdmX E3 ligase inhibitors using a cell-based ubiquitination assay.},
	journal = {Cancer Discov},
	volume = {1},
	number = {4},
	year = {2011},
	month = {2011 Sep},
	pages = {312-25},
	abstract = {E3 ubiquitin ligases are of interest as drug targets for their ability to regulate protein stability and function. The oncogene Mdm2 is an attractive E3 ligase to target, as it is the key negative regulator of the tumor suppressor p53, which controls the transcription of genes involved in cell fate. Overexpression of Mdm2 facilitates tumorigenesis by inactivating p53, and through p53-independent oncogenic effects. We developed a high-throughput cellular Mdm2 auto-ubiquitination assay, which we used to discover a class of small-molecule Mdm2 ligase activity inhibitors. These compounds inhibit Mdm2 and p53 ubiquitination in cells, reduce viability of cells with wild-type p53, and synergize with DNA-damaging agents to cause cell death. We determined that these compounds effectively inhibit the E3 ligase activity of the Mdm2-MdmX hetero-complex. This mechanism may be exploitable to create a new class of anti-tumor agents.},
	keywords = {Apoptosis, Cell Line, Tumor, Cell Survival, DNA Damage, Enzyme Inhibitors, HCT116 Cells, High-Throughput Screening Assays, Humans, Nuclear Proteins, Oncogenes, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-mdm2, Transcription, Genetic, Tumor Suppressor Protein p53, Ubiquitin-Protein Ligases, Ubiquitination},
	issn = {2159-8290},
	doi = {10.1158/2159-8290.CD-11-0104},
	author = {Herman, Ariel G and Hayano, Miki and Poyurovsky, Masha V and Shimada, Kenichi and Skouta, Rachid and Prives, Carol and Stockwell, Brent R.}
}
@article {472971,
	title = {Modulatory profiling identifies mechanisms of small molecule-induced cell death.},
	journal = {Proc Natl Acad Sci U S A},
	volume = {108},
	number = {39},
	year = {2011},
	month = {2011 Sep 27},
	pages = {E771-80},
	abstract = {Cell death is a complex process that plays a vital role in development, homeostasis, and disease. Our understanding of and ability to control cell death is impeded by an incomplete characterization of the full range of cell death processes that occur in mammalian systems, especially in response to exogenous perturbations. We present here a general approach to address this problem, which we call modulatory profiling. Modulatory profiles are composed of the changes in potency and efficacy of lethal compounds produced by a second cell death-modulating agent in human cell lines. We show that compounds with the same characterized mechanism of action have similar modulatory profiles. Furthermore, clustering of modulatory profiles revealed relationships not evident when clustering lethal compounds based on gene expression profiles alone. Finally, modulatory profiling of compounds correctly predicted three previously uncharacterized compounds to be microtubule-destabilizing agents, classified numerous compounds that act nonspecifically, and identified compounds that cause cell death through a mechanism that is morphologically and biochemically distinct from previously established ones.},
	keywords = {bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein, Cell Death, Cell Line, Humans, Microtubules, Signal Transduction},
	issn = {1091-6490},
	doi = {10.1073/pnas.1106149108},
	author = {Wolpaw, Adam J and Shimada, Kenichi and Skouta, Rachid and Welsch, Matthew E and Akavia, Uri David and Pe{\textquoteright}er, Dana and Shaik, Fatima and Bulinski, J Chloe and Stockwell, Brent R.}
}
@article {472976,
	title = {Transdermal delivery of a readthrough-inducing drug: a new approach of gentamicin administration for the treatment of nonsense mutation-mediated disorders.},
	journal = {J Biochem},
	volume = {147},
	number = {4},
	year = {2010},
	month = {2010 Apr},
	pages = {463-70},
	abstract = {To induce the readthrough of premature termination codons, aminoglycoside antibiotics such as gentamicin have attracted interest as potential therapeutic agents for diseases caused by nonsense mutations. The transdermal delivery of gentamicin is considered unfeasible because of its low permeability through the dermis. However, if the skin permeability of gentamicin could be improved, it would allow topical application without the need for systemic delivery. In this report, we demonstrated that the skin permeability of gentamicin increased with the use of a thioglycolate-based depilatory agent. After transdermal administration, the readthrough activity in skeletal muscle, as determined using a lacZ/luc reporter system, was found to be equivalent to systemic administration when measured in transgenic mice. Transdermally applied gentamicin was detected by liquid chromatography-tandem mass spectrometry in the muscles and sera of mice only after depilatory agent-treatment. In addition, expansion of the intercellular gaps in the basal and prickle-cell layers was observed by electron microscopy only in the depilatory agent-treated mice. Depilatory agent-treatment may be useful for the topical delivery of readthough-inducing drugs for the rescue of nonsense mutation-mediated genetic disorders. This finding may also be applicable for the transdermal delivery of other pharmacologically active molecules.},
	keywords = {Administration, Cutaneous, Animals, Basement Membrane, Codon, Nonsense, Dystrophin, Epidermis, Extracellular Space, Gene Expression Regulation, Enzymologic, Genes, Reporter, Genetic Diseases, Inborn, Gentamicins, Hair Removal, Male, Mice, Mice, Hairless, Mice, Transgenic, Muscle, Skeletal, Permeability, Protein Biosynthesis, Skin Physiological Phenomena, Thioglycolates, Tissue Distribution, Whole Body Imaging},
	issn = {1756-2651},
	doi = {10.1093/jb/mvp185},
	author = {Shiozuka, Masataka and Wagatsuma, Akira and Kawamoto, Tadafumi and Sasaki, Hiroyuki and Shimada, Kenichi and Takahashi, Yoshikazu and Nonomura, Yoshiaki and Matsuda, Ryoichi}
}
