Person: Schreiber, Stuart
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Schreiber
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Stuart
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Schreiber, Stuart
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Publication Small-Molecule Targeting of Brachyury Transcription Factor Addiction in Chordoma(Springer Science and Business Media LLC, 2019-01-21) Sharifnia, Tanaz; Wawer, Mathias J.; Chen, Ting; Huang, Qing-Yuan; Weir, Barbara A.; Sizemore, Ann; Lawlor, Matthew A.; Goodale, Amy; Cowley, Glenn S.; Vazquez, Francisca; Ott, Christopher; Francis, Joshua M.; Sassi, Slim; Cogswell, Patricia; Sheppard, Hadley E.; Zhang, Tinghu; Gray, Nathanael; Clarke, Paul A.; Blagg, Julian; Workman, Paul; Sommer, Josh; Hornicek, Francis; Root, David E.; Hahn, William; Bradner, James E.; Wong, Kwok-Kin; Clemons, Paul A.; Lin, Charles Y.; Kotz, Joanne D.; Schreiber, StuartChordoma is a primary bone cancer with no approved therapy. The identification of therapeutic targets in this disease has been challenging due to the infrequent occurrence of clinically actionable somatic mutations in chordoma tumors. Here we describe the discovery of therapeutically targetable chordoma dependencies via genome-scale CRISPR-Cas9 screening and focused small-molecule sensitivity profiling. These systematic approaches reveal that the developmental transcription factor T (brachyury; TBXT) is the top selectively essential gene in chordoma, and that transcriptional cyclin-dependent kinase (CDK) inhibitors targeting CDK7/12/13 and CDK9 potently suppress chordoma cell proliferation. In other cancer types, transcriptional CDK inhibitors have been observed to downregulate highly expressed, enhancer-associated oncogenic transcription factors. In chordoma, we find that T is associated with a 1.5-Mb region containing ‘super-enhancers’ and is the most highly expressed super-enhancer-associated transcription factor. Notably, transcriptional CDK inhibition leads to preferential and concentration-dependent downregulation of cellular brachyury protein levels in all models tested. In vivo, CDK7/12/13-inhibitor treatment substantially reduces tumor growth. Together, these data demonstrate small-molecule targeting of brachyury transcription factor addiction in chordoma, identify a mechanism of T gene regulation that underlies this therapeutic strategy, and provide a blueprint for applying systematic genetic and chemical screening approaches to discover vulnerabilities in genomically quiet cancers.Publication Chemical perturbation of an intrinsically disordered region of TFIID distinguishes two modes of transcription initiation(eLife Sciences Publications, Ltd, 2015) Zhang, Zhengjian; Boskovic, Zarko; Hussain, Mahmud M; Hu, Wenxin; Inouye, Carla; Kim, Han-Je; Abole, A Katherine; Doud, Mary K; Lewis, Timothy A; Koehler, Angela N; Schreiber, Stuart; Tjian, RobertIntrinsically disordered proteins/regions (IDPs/IDRs) are proteins or peptide segments that fail to form stable 3-dimensional structures in the absence of partner proteins. They are abundant in eukaryotic proteomes and are often associated with human diseases, but their biological functions have been elusive to study. In this study, we report the identification of a tin(IV) oxochloride-derived cluster that binds an evolutionarily conserved IDR within the metazoan TFIID transcription complex. Binding arrests an isomerization of promoter-bound TFIID that is required for the engagement of Pol II during the first (de novo) round of transcription initiation. However, the specific chemical probe does not affect reinitiation, which requires the re-entry of Pol II, thus, mechanistically distinguishing these two modes of transcription initiation. This work also suggests a new avenue for targeting the elusive IDRs by harnessing certain features of metal-based complexes for mechanistic studies, and for the development of novel pharmaceutical interventions. DOI: http://dx.doi.org/10.7554/eLife.07777.001Publication CTD2 Dashboard: a searchable web interface to connect validated results from the Cancer Target Discovery and Development Network(Oxford University Press, 2017) Aksoy, Bülent Arman; Dančík, Vlado; Smith, Kenneth; Mazerik, Jessica N.; Ji, Zhou; Gross, Benjamin; Nikolova, Olga; Jaber, Nadia; Califano, Andrea; Schreiber, Stuart; Gerhard, Daniela S.; Hermida, Leandro C.; Jagu, Subhashini; Sander, Chris; Floratos, Aris; Clemons, Paul A.Abstract The Cancer Target Discovery and Development (CTD2) Network aims to use functional genomics to accelerate the translation of high-throughput and high-content genomic and small-molecule data towards use in precision oncology. As part of this goal, and to share its conclusions with the research community, the Network developed the ‘CTD2 Dashboard’ [https://ctd2-dashboard.nci.nih.gov/], which compiles CTD2 Network-generated conclusions, termed ‘observations’, associated with experimental entities, collected by its member groups (‘Centers’). Any researcher interested in learning about a given gene, protein, or compound (a ‘subject’) studied by the Network can come to the CTD2 Dashboard to quickly and easily find, review, and understand Network-generated experimental results. In particular, the Dashboard allows visitors to connect experiments about the same target, biomarker, etc., carried out by multiple Centers in the Network. The Dashboard’s unique knowledge representation allows information to be compiled around a subject, so as to become greater than the sum of the individual contributions. The CTD2 Network has broadly defined levels of validation for evidence (‘Tiers’) pertaining to a particular finding, and the CTD2 Dashboard uses these Tiers to indicate the extent to which results have been validated. Researchers can use the Network’s insights and tools to develop a new hypothesis or confirm existing hypotheses, in turn advancing the findings towards clinical applications. Database URL: https://ctd2-dashboard.nci.nih.gov/Publication Efficient Routes to a Diverse Array of Amino Alcohol-Derived Chiral Fragments(American Chemical Society, 2016) Haftchenary, Sina; Nelson, Shawn; Furst, Laura; Dandapani, Sivaraman; Ferrara, Steven J.; Bošković, Žarko V.; Figueroa Lazú, Samuel; Guerrero, Adrian M.; Serrano, Juan C.; Crews, DeMarcus K.; Brackeen, Cristina; Mowat, Jeffrey; Brumby, Thomas; Bauser, Marcus; Schreiber, Stuart; Phillips, Andrew J.Efficient syntheses of chiral fragments derived from chiral amino alcohols are described. Several unique scaffolds were readily accessed in 1–5 synthetic steps leading to 45 chiral fragments, including oxazolidinones, morpholinones, lactams, and sultams. These fragments have molecular weights ranging from 100 to 255 Da and are soluble in water (0.085 to >15 mM).Publication Synthesis of a Bicyclic Azetidine with In Vivo Antimalarial Activity Enabled by Stereospecific, Directed C(sp3)–H Arylation(American Chemical Society, 2017) Maetani, Micah; Zoller, Jochen; Melillo, Bruno; Verho, Oscar; Kato, Nobutaka; Pu, Jun; Comer, Eamon; Schreiber, StuartThe development of new antimalarial therapeutics is necessary to address the increasing resistance to current drugs. Bicyclic azetidines targeting Plasmodium falciparum phenylalanyl-tRNA synthetase comprise one promising new class of antimalarials, especially due to their activities against three stages of the parasite’s life cycle, but a lengthy synthetic route to these compounds may affect the feasibility of delivering new therapeutic agents within the cost constraints of antimalarial drugs. Here, we report an efficient synthesis of antimalarial compound BRD3914 (EC50 = 15 nM) that hinges on a Pd-catalyzed, directed C(sp3)–H arylation of azetidines at the C3 position. This newly developed protocol exhibits a broad substrate scope and provides access to valuable, stereochemically defined building blocks. BRD3914 was evaluated in P. falciparum-infected mice, providing a cure after four oral doses.Publication Discovery of Small-Molecule Modulators of the Sonic Hedgehog Pathway(American Chemical Society, 2013) Schaefer, Giannina I.; Perez, José R.; Duvall, Jeremy R.; Stanton, Benjamin Z.; Shamji, Alykhan F.; Schreiber, StuartThe Hedgehog signaling pathway is involved in the development of multicellular organisms and, when deregulated, can contribute to certain cancers, among other diseases. The molecular characterization of the pathway, which has been enabled by small-molecule probes targeting its components, remains incomplete. Here, we report the discovery of two potent, small-molecule inhibitors of the Sonic Hedgehog (Shh) pathway, BRD50837 and BRD9526. Both compounds exhibit stereochemistry-based structure–activity relationships, a feature suggestive of a specific and selective interaction of the compounds with as-yet-unknown cellular target(s) and made possible by the strategy used to synthesize them as members of a stereochemically and skeletally diverse screening collection. The mechanism-of-action of these compounds in some ways shares similarities to that of cyclopamine, a commonly used pathway inhibitor. Yet, in other ways their mechanism-of-action is strikingly distinct. We hope that these novel compounds will be useful probes of this complex signaling pathway.Publication An Interactive Resource to Identify Cancer Genetic and Lineage Dependencies Targeted by Small Molecules(Elsevier BV, 2013) Basu, Amrita; Bodycombe, Nicole E.; Cheah, Jaime H.; Price, Edmund V.; Liu, Ke; Schaefer, Giannina Ines; Ebright, Richard; Stewart, Michelle L.; Ito, Daisuke; Wang, Stephanie; Bracha, Abigail L.; Liefeld, Ted; Wawer, Mathias; Gilbert, Joshua C.; Wilson, Andrew J.; Stransky, Nicolas; Kryukov, Gregory V.; Dancik, Vlado; Barretina, Jordi; Garraway, Levi; Hon, C. Suk-Yee; Munoz, Benito; Bittker, Joshua A.; Stockwell, Brent R.; Khabele, Dineo; Stern, Andrew M.; Clemons, Paul A.; Shamji, Alykhan F.; Schreiber, StuartThe high rate of clinical response to protein-kinase-targeting drugs matched to cancer patients with specific genomic alterations has prompted efforts to use cancer cell line (CCL) profiling to identify additional biomarkers of small-molecule sensitivities. We have quantitatively measured the sensitivity of 242 genomically characterized CCLs to an Informer Set of 354 small molecules that target many nodes in cell circuitry, uncovering protein dependencies that: (1) associate with specific cancer-genomic alterations and (2) can be targeted by small molecules. We have created the Cancer Therapeutics Response Portal (http://www.broadinstitute.org/ctrp) to enable users to correlate genetic features to sensitivity in individual lineages and control for confounding factors of CCL profiling. We report a candidate dependency, associating activating mutations in the oncogene β-catenin with sensitivity to the Bcl-2 family antagonist, navitoclax. The resource can be used to develop novel therapeutic hypotheses and to accelerate discovery of drugs matched to patients by their cancer genotype and lineage.Publication Multiplex Cytological Profiling Assay to Measure Diverse Cellular States(Public Library of Science, 2013) Gustafsdottir, Sigrun M.; Ljosa, Vebjorn; Sokolnicki, Katherine L.; Anthony Wilson, J.; Walpita, Deepika; Kemp, Melissa M.; Petri Seiler, Kathleen; Carrel, Hyman A.; Golub, Todd; Schreiber, Stuart; Clemons, Paul A.; Carpenter, Anne E.; Shamji, Alykhan F.Computational methods for image-based profiling are under active development, but their success hinges on assays that can capture a wide range of phenotypes. We have developed a multiplex cytological profiling assay that “paints the cell” with as many fluorescent markers as possible without compromising our ability to extract rich, quantitative profiles in high throughput. The assay detects seven major cellular components. In a pilot screen of bioactive compounds, the assay detected a range of cellular phenotypes and it clustered compounds with similar annotated protein targets or chemical structure based on cytological profiles. The results demonstrate that the assay captures subtle patterns in the combination of morphological labels, thereby detecting the effects of chemical compounds even though their targets are not stained directly. This image-based assay provides an unbiased approach to characterize compound- and disease-associated cell states to support future probe discovery.Publication Small Molecules Efficiently Direct Endodermal Differentiation of Mouse and Human Embryonic Stem Cells(Elsevier, 2009) Borowiak, Malgorzata; Maehr, René; Chen, Shuibing; Chen, Alice E.; Tang, Weiping; Fox, Julia L.; Schreiber, Stuart; Melton, DouglasAn essential step for therapeutic and research applications of stem cells is the ability to differentiate them into specific cell types. Endodermal cell derivatives, including lung, liver, and pancreas, are of interest for regenerative medicine, but efforts to produce these cells have been met with only modest success. In a screen of 4000 compounds, two cell-permeable small molecules were indentified that direct differentiation of ESCs into the endodermal lineage. These compounds induce nearly 80% of ESCs to form definitive endoderm, a higher efficiency than that achieved by Activin A or Nodal, commonly used protein inducers of endoderm. The chemically induced endoderm expresses multiple endodermal markers, can participate in normal development when injected into developing embryos, and can form pancreatic progenitors. The application of small molecules to differentiate mouse and human ESCs into endoderm represents a step toward achieving a reproducible and efficient production of desired ESC derivatives.Publication A small molecule that directs differentiation of human ESCs into the pancreatic lineage(Nature Publishing Group, 2009) Chen, Shuibing; Borowiak, Malgorzata; Maehr, René; Osafune, Kenji; Davidow, Lance; Lam, Kelvin; Peng, Lee F; Schreiber, Stuart; Rubin, Lee; Melton, DouglasStepwise differentiation from embryonic stem cells (ESCs) to functional insulin-secreting beta cells will identify key steps in beta-cell development and may yet prove useful for transplantation therapy for diabetics. An essential step in this schema is the generation of pancreatic progenitors—cells that express Pdx1 and produce all the cell types of the pancreas. High-content chemical screening identified a small molecule, (-)-indolactam V, that induces differentiation of a substantial number of Pdx1-expressing cells from human ESCs. The Pdx1-expressing cells express other pancreatic markers and contribute to endocrine, exocrine and duct cells, in vitro and in vivo. Further analyses showed that (-)-indolactam V works specifically at one stage of pancreatic development, inducing pancreatic progenitors from definitive endoderm. This study describes a chemical screening platform to investigate human ESC differentiation and demonstrates the generation of a cell population that is a key milepost on the path to making beta cells.