Bio

Current Role at Stanford


Director, High-Throughput Bioscience Center

The High-Throughput Bioscience Center's mission is to provide researchers at Stanford with the ability to run high-throughput chemical, siRNA, cDNA, and high-content screens for the purpose of drug and/or target discovery. The HTBC is a Stanford University School of Medicine core facility and was created in 2003 by the Department of Chemical and Systems Biology (formerly Molecular Pharmacology). The HTBC is a shared resource (Bioscience Screening Facility) for the Stanford Cancer Institute (more info), the Digestive Disease Center (Chemical Genomics Core), and the NIH Clinical and Translational Science Award (Spectrum).

Research approaches that were previously done exclusively in industry are now being used in academia to advance basic research. This high-throughput screening (HTS) laboratory allows Stanford researchers and others to discover novel modulators of targets that otherwise would not be practical in industry. The center incorporates instrumentation (purchased with NCRR NIH Instrumentation grant numbers S10RR019513 and S10RR026338), databases, compound libraries, and personnel whose previous sole domains were in industry. Among our instrumentation are a Molecular Devices ImageXpress Micro High-Content fluorescence microplate imager, with live cell and phase contrast/brightfield options, a Caliper Life Sciences SciClone ALH3000 and an Agilent Bravo microplate liquid handler, and the Molecular Devices Analyst GT and FlexStation II 384 and Tecan Infinite M1000 fluorescence, luminescence and absorbance multimode microplate readers. We have over 130,000 small molecules for compound screens, 15,000 cDNAs for genomic screens, and the siARRAY whole human genome siRNA library from ThermoFisher Scientific (formerly Dharmacon) targeting 21,000 genes.

The HTBC is located in CCSR Room 0133-North Wing, between the Transgenic Mouse Facility, the Immune Monitoring Core, and the Stanford Functional Genomics Facility.

Education & Certifications


  • PhD, University of California, Berkeley, Molecular and Cellular Biology (1995)
  • BS, MIT, Applied Biology (1990)

Professional

Professional Interests


High-Throughput Screening of small molecule drug libraries and whole genome human and mouse siRNA libraries.

Professional Affiliations and Activities


  • Member, Cancer Institute (2008 - Present)

Publications

Journal Articles


  • Next-Generation NAMPT Inhibitors Identified by Sequential High-Throughput Phenotypic Chemical and Functional Genomic Screens. Chemistry & biology Matheny, C. J., Wei, M. C., Bassik, M. C., Donnelly, A. J., Kampmann, M., Iwasaki, M., Piloto, O., Solow-Cordero, D. E., Bouley, D. M., Rau, R., Brown, P., McManus, M. T., Weissman, J. S., Cleary, M. L. 2013; 20 (11): 1352-1363

    Abstract

    Phenotypic high-throughput chemical screens allow for discovery of small molecules that modulate complex phenotypes and provide lead compounds for novel therapies; however, identification of the mechanistically relevant targets remains a major experimental challenge. We report the application of sequential unbiased high-throughput chemical and ultracomplex small hairpin RNA (shRNA) screens to identify a distinctive class of inhibitors that target nicotinamide phosphoribosyl transferase (NAMPT), a rate-limiting enzyme in the biosynthesis of nicotinamide adenine dinucleotide, a crucial cofactor in many biochemical processes. The lead compound STF-118804 is a highly specific NAMPT inhibitor, improves survival in an orthotopic xenotransplant model of high-risk acute lymphoblastic leukemia, and targets leukemia stem cells. Tandem high-throughput screening using chemical and ultracomplex shRNA libraries, therefore, provides a rapid chemical genetics approach for seamless progression from small-molecule lead identification to target discovery and validation.

    View details for DOI 10.1016/j.chembiol.2013.09.014

    View details for PubMedID 24183972

  • A c-Myc Activation Sensor-Based High-Throughput Drug Screening Identifies an Antineoplastic Effect of Nitazoxanide. Molecular cancer therapeutics Fan-Minogue, H., Bodapati, S., Solow-Cordero, D., Fan, A., Paulmurugan, R., Massoud, T. F., Felsher, D. W., Gambhir, S. S. 2013; 12 (9): 1896-1905

    Abstract

    Deregulation of c-Myc plays a central role in the tumorigenesis of many human cancers. Yet, the development of drugs regulating c-Myc activity has been challenging. To facilitate the identification of c-Myc inhibitors, we developed a molecular imaging sensor based high throughput-screening (HTS) system. This system uses a cell-based assay to detect c-Myc activation in a HTS format, which is established from a pure clone of a stable breast cancer cell line that constitutively expresses a c-Myc activation sensor. Optimization of the assay performance in the HTS format resulted in uniform and robust signals at the baseline. Using this system, we performed a quantitative HTS against approximately 5,000 existing bioactive compounds from five different libraries. Thirty-nine potential hits were identified, including currently known c-Myc inhibitors. There are a few among the top potent hits that are not known for anti-c-Myc activity. One of these hits is nitazoxanide (NTZ), a thiazolide for treating human protozoal infections. Validation of NTZ in different cancer cell lines revealed a high potency for c-Myc inhibition with IC50 ranging between 10 - 500nM. Oral administration of NTZ in breast cancer xenograft mouse models significantly suppressed tumor growth by inhibition of c-Myc and induction of apoptosis. These findings suggest a potential of NTZ to be repurposed as a new anti-tumor agent for inhibition of c-Myc associated neoplasia. Our work also demonstrated the unique advantage of molecular imaging in accelerating discovery of drugs for c-Myc targeted cancer therapy.

    View details for DOI 10.1158/1535-7163.MCT-12-1243

    View details for PubMedID 23825064

  • FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension. The Journal of clinical investigation Spiekerkoetter, E., Tian, X., Cai, J., Hopper, R. K., Sudheendra, D., Li, C. G., El-Bizri, N., Sawada, H., Haghighat, R., Chan, R., Haghighat, L., de Jesus Perez, V., Wang, L., Reddy, S., Zhao, M., Bernstein, D., Solow-Cordero, D. E., Beachy, P. A., Wandless, T. J., Dijke, P. T., Rabinovitch, M. 2013

    Abstract

    Dysfunctional bone morphogenetic protein receptor-2 (BMPR2) signaling is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). We used a transcriptional high-throughput luciferase reporter assay to screen 3,756 FDA-approved drugs and bioactive compounds for induction of BMPR2 signaling. The best response was achieved with FK506 (tacrolimus), via a dual mechanism of action as a calcineurin inhibitor that also binds FK-binding protein-12 (FKBP12), a repressor of BMP signaling. FK506 released FKBP12 from type I receptors activin receptor-like kinase 1 (ALK1), ALK2, and ALK3 and activated downstream SMAD1/5 and MAPK signaling and ID1 gene regulation in a manner superior to the calcineurin inhibitor cyclosporine and the FKBP12 ligand rapamycin. In pulmonary artery endothelial cells (ECs) from patients with idiopathic PAH, low-dose FK506 reversed dysfunctional BMPR2 signaling. In mice with conditional Bmpr2 deletion in ECs, low-dose FK506 prevented exaggerated chronic hypoxic PAH associated with induction of EC targets of BMP signaling, such as apelin. Low-dose FK506 also reversed severe PAH in rats with medial hypertrophy following monocrotaline and in rats with neointima formation following VEGF receptor blockade and chronic hypoxia. Our studies indicate that low-dose FK506 could be useful in the treatment of PAH.

    View details for PubMedID 23867624

  • Design and synthesis of procollagen C-proteinase inhibitors BIOORGANIC & MEDICINAL CHEMISTRY LETTERS Turtle, E., Chow, N., Yang, C., Sosa, S., Bauer, U., Brenner, M., Solow-Cordero, D., Ho, W. 2012; 22 (24): 7397-7401

    Abstract

    Non-peptidic inhibitors of procollagen C-proteinase (PCP) were designed from substrate leads. Compounds were optimized for potency and selectivity, with N-substituted aryl sulfonamide hydroxamates having the best combination of these properties. Compounds 89 and 60 have IC(50) values of 10 and 80 nM, respectively, against PCP; excellent selectivity over MMP's 1, 2, and 9; and activity in cell-based collagen deposition assays.

    View details for DOI 10.1016/j.bmcl.2012.10.067

    View details for Web of Science ID 000311425500021

    View details for PubMedID 23134659

  • Discovery and validation of small-molecule heat-shock protein 90 inhibitors through multimodality molecular imaging in living subjects PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Chan, C. T., Reeves, R. E., Geller, R., Yaghoubi, S. S., Hoehne, A., Solow-Cordero, D. E., Chiosis, G., Massoud, T. F., Paulmurugan, R., Gambhir, S. S. 2012; 109 (37): E2476-E2485

    Abstract

    Up-regulation of the folding machinery of the heat-shock protein 90 (Hsp90) chaperone protein is crucial for cancer progression. The two Hsp90 isoforms (? and ?) play different roles in response to chemotherapy. To identify isoform-selective inhibitors of Hsp90(?/?)/cochaperone p23 interactions, we developed a dual-luciferase (Renilla and Firefly) reporter system for high-throughput screening (HTS) and monitoring the efficacy of Hsp90 inhibitors in cell culture and live mice. HTS of a 30,176 small-molecule chemical library in cell culture identified a compound, N-(5-methylisoxazol-3-yl)-2-[4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidin-2-ylthio]acetamide (CP9), that binds to Hsp90(?/?) and displays characteristics of Hsp90 inhibitors, i.e., degradation of Hsp90 client proteins and inhibition of cell proliferation, glucose metabolism, and thymidine kinase activity, in multiple cancer cell lines. The efficacy of CP9 in disrupting Hsp90(?/?)/p23 interactions and cell proliferation in tumor xenografts was evaluated by non-invasive, repetitive Renilla luciferase and Firefly luciferase imaging, respectively. At 38 h posttreatment (80 mg/kg × 3, i.p.), CP9 led to selective disruption of Hsp90?/p23 as compared with Hsp90?/p23 interactions. Small-animal PET/CT in the same cohort of mice showed that CP9 treatment (43 h) led to a 40% decrease in (18)F-fluorodeoxyglucose uptake in tumors relative to carrier control-treated mice. However, CP9 did not lead to significant degradation of Hsp90 client proteins in tumors. We performed a structural activity relationship study with 62 analogs of CP9 and identified A17 as the lead compound that outperformed CP9 in inhibiting Hsp90(?/?)/p23 interactions in cell culture. Our efforts demonstrated the power of coupling of HTS with multimodality molecular imaging and led to identification of Hsp90 inhibitors.

    View details for DOI 10.1073/pnas.1205459109

    View details for Web of Science ID 000309208000012

    View details for PubMedID 22895790

  • Targeting GLUT1 and the Warburg Effect in Renal Cell Carcinoma by Chemical Synthetic Lethality SCIENCE TRANSLATIONAL MEDICINE Chan, D. A., Sutphin, P. D., Nguyen, P., Turcotte, S., Lai, E. W., Banh, A., Reynolds, G. E., Chi, J., Wu, J., Solow-Cordero, D. E., Bonnet, M., Flanagan, J. U., Bouley, D. M., Graves, E. E., Denny, W. A., Hay, M. P., Giaccia, A. J. 2011; 3 (94)

    Abstract

    Identifying new targeted therapies that kill tumor cells while sparing normal tissue is a major challenge of cancer research. Using a high-throughput chemical synthetic lethal screen, we sought to identify compounds that exploit the loss of the von Hippel-Lindau (VHL) tumor suppressor gene, which occurs in about 80% of renal cell carcinomas (RCCs). RCCs, like many other cancers, are dependent on aerobic glycolysis for ATP production, a phenomenon known as the Warburg effect. The dependence of RCCs on glycolysis is in part a result of induction of glucose transporter 1 (GLUT1). Here, we report the identification of a class of compounds, the 3-series, exemplified by STF-31, which selectively kills RCCs by specifically targeting glucose uptake through GLUT1 and exploiting the unique dependence of these cells on GLUT1 for survival. Treatment with these agents inhibits the growth of RCCs by binding GLUT1 directly and impeding glucose uptake in vivo without toxicity to normal tissue. Activity of STF-31 in these experimental renal tumors can be monitored by [(18)F]fluorodeoxyglucose uptake by micro-positron emission tomography imaging, and therefore, these agents may be readily tested clinically in human tumors. Our results show that the Warburg effect confers distinct characteristics on tumor cells that can be selectively targeted for therapy.

    View details for DOI 10.1126/scitranslmed.3002394

    View details for Web of Science ID 000293459700004

    View details for PubMedID 21813754

  • Identification of an Ire1alpha endonuclease specific inhibitor with cytotoxic activity against human multiple myeloma BLOOD Papandreou, I., Denko, N. C., Olson, M., Van Melckebeke, H., Lust, S., Tam, A., Solow-Cordero, D. E., Bouley, D. M., Offner, F., Niwa, M., Koong, A. C. 2011; 117 (4): 1311-1314

    Abstract

    Activation of the adaptive Ire1-XBP1 pathway has been identified in many solid tumors and hematologic malignancies, including multiple myeloma (MM). Here, we report the identification of STF-083010, a novel small-molecule inhibitor of Ire1. STF-083010 inhibited Ire1 endonuclease activity, without affecting its kinase activity, after endoplasmic reticulum stress both in vitro and in vivo. Treatment with STF-083010 showed significant antimyeloma activity in model human MM xenografts. Similarly, STF-083010 was preferentially toxic to freshly isolated human CD138(+) MM cells compared with other similarly isolated cell populations. The identification of this novel Ire1 inhibitor supports the hypothesis that the Ire1-XBP1 axis is a promising target for anticancer therapy, especially in the context of MM.

    View details for DOI 10.1182/blood-2010-08-303099

    View details for Web of Science ID 000286623400029

    View details for PubMedID 21081713

  • Small-molecule inhibitors reveal multiple strategies for Hedgehog pathway blockade PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Hyman, J. M., Firestone, A. J., Heine, V. M., Zhao, Y., Ocasio, C. A., Han, K., Sun, M., Rack, P. G., Sinha, S., Wu, J. J., Solow-Cordero, D. E., Jiang, J., Rowitch, D. H., Chen, J. K. 2009; 106 (33): 14132-14137

    Abstract

    Inappropriate activation of the Hedgehog (Hh) signaling pathway has been implicated in a diverse spectrum of cancers, and its pharmacological blockade has emerged as an anti-tumor strategy. While nearly all known Hh pathway antagonists target the transmembrane protein Smoothened (Smo), small molecules that suppress downstream effectors could more comprehensively remediate Hh pathway-dependent tumors. We report here four Hh pathway antagonists that are epistatic to the nucleocytoplasmic regulator Suppressor of Fused [Su(fu)], including two that can inhibit Hh target gene expression induced by overexpression of the Gli transcription factors. Each inhibitor has a unique mechanism of action, and their phenotypes reveal that Gli processing, Gli activation, and primary cilia formation are pharmacologically targetable. We further establish the ability of certain compounds to block the proliferation of cerebellar granule neuron precursors expressing an oncogenic form of Smo, and we demonstrate that Hh pathway inhibitors can have tissue-specific activities. These antagonists therefore constitute a valuable set of chemical tools for interrogating downstream Hh signaling mechanisms and for developing chemotherapies against Hh pathway-related cancers.

    View details for DOI 10.1073/pnas.0907134106

    View details for Web of Science ID 000269078700091

    View details for PubMedID 19666565

  • A Genome-wide siRNA Screen Reveals Diverse Cellular Processes and Pathways that Mediate Genome Stability MOLECULAR CELL Paulsen, R. D., Soni, D. V., Wollman, R., Hahn, A. T., Yee, M., Guan, A., Hesley, J. A., Miller, S. C., Cromwell, E. F., Solow-Cordero, D. E., Meyer, T., Cimprich, K. A. 2009; 35 (2): 228-239

    Abstract

    Signaling pathways that respond to DNA damage are essential for the maintenance of genome stability and are linked to many diseases, including cancer. Here, a genome-wide siRNA screen was employed to identify additional genes involved in genome stabilization by monitoring phosphorylation of the histone variant H2AX, an early mark of DNA damage. We identified hundreds of genes whose downregulation led to elevated levels of H2AX phosphorylation (gammaH2AX) and revealed links to cellular complexes and to genes with unclassified functions. We demonstrate a widespread role for mRNA-processing factors in preventing DNA damage, which in some cases is caused by aberrant RNA-DNA structures. Furthermore, we connect increased gammaH2AX levels to the neurological disorder Charcot-Marie-Tooth (CMT) syndrome, and we find a role for several CMT proteins in the DNA-damage response. These data indicate that preservation of genome stability is mediated by a larger network of biological processes than previously appreciated.

    View details for DOI 10.1016/j.molcel.2009.06.021

    View details for Web of Science ID 000268643700011

    View details for PubMedID 19647519

  • Molecular Imaging of Phosphorylation Events for Drug Development MOLECULAR IMAGING AND BIOLOGY CHAN, C. T., Paulmurugan, R., Reeves, R. E., Solow-Cordero, D., Gambhir, S. S. 2009; 11 (3): 144-158

    Abstract

    Protein phosphorylation mediated by protein kinases controls numerous cellular processes. A genetically encoded, generalizable split firefly luciferase (FL)-assisted complementation system was developed for noninvasive monitoring phosphorylation events and efficacies of kinase inhibitors in cell culture and in small living subjects by optical bioluminescence imaging.An Akt sensor (AST) was constructed to monitor Akt phosphorylation and the effect of different PI-3K and Akt inhibitors. Specificity of AST was determined using a non-phosphorylable mutant sensor containing an alanine substitution (ASA).The PI-3K inhibitor LY294002 and Akt kinase inhibitor perifosine led to temporal- and dose-dependent increases in complemented FL activities in 293T human kidney cancer cells stably expressing AST (293T/AST) but not in 293T/ASA cells. Inhibition of endogenous Akt phosphorylation and kinase activities by perifosine also correlated with increase in complemented FL activities in 293T/AST cells but not in 293T/ASA cells. Treatment of nude mice bearing 293T/AST xenografts with perifosine led to a 2-fold increase in complemented FL activities compared to that of 293T/ASA xenografts. Our system was used to screen a small chemical library for novel modulators of Akt kinase activity.This generalizable approach for noninvasive monitoring of phosphorylation events will accelerate the discovery and validation of novel kinase inhibitors and modulators of phosphorylation events.

    View details for DOI 10.1007/s11307-008-0187-7

    View details for Web of Science ID 000265686900002

    View details for PubMedID 19048345

  • Transforming growth factor-beta regulation of bone morphogenetic protein-1 procollagen C-proteinase and related proteins in fibrogenic cells and keratinocytes JOURNAL OF BIOLOGICAL CHEMISTRY Lee, S. B., SOLOWCORDERO, D. E., Kessler, E., TAKAHARA, K., Greenspan, D. S. 1997; 272 (30): 19059-19066

    Abstract

    Transforming growth factor-beta1 (TGF-beta1) induces increased extracellular matrix deposition. Bone morphogenetic protein-1 (BMP-1) also plays key roles in regulating vertebrate matrix deposition; it is the procollagen C-proteinase (PCP) that processes procollagen types I-III, and it may also mediate biosynthetic processing of lysyl oxidase and laminin 5. Here we show that BMP-1 is itself up-regulated by TGF-beta1 and that secreted BMP-1, induced by TGF-beta1, is either processed to an active form or remains as unprocessed proenzyme, in a cell type-dependent manner. In MG-63 osteosacrcoma cells, TGF-beta1 elevated levels of BMP-1 mRNA approximately 7-fold and elevated levels of mRNA for mammalian tolloid (mTld), an alternatively spliced product of the BMP1 gene, to a lesser extent. Induction of RNA was dose- and time-dependent and cycloheximide-inhibitable. Secreted BMP-1 and mTld, induced by TGF-beta1 in MG-63 and other fibrogenic cell cultures, were predominantly in forms in which proregions had been removed to yield activated enzyme. TGF-beta1 treatment also induced procollagen N-proteinase activity in fibrogenic cultures, while expression of the procollagen C-proteinase enhancer (PCPE), a glycoprotein that stimulates PCP activity, was unaffected. In contrast to fibrogenic cells, keratinocytes lacked detectable PCPE under any culture conditions and were induced by TGF-beta1 to secrete BMP-1 and mTld predominantly as unprocessed proenzymes.

    View details for Web of Science ID A1997XM34200081

    View details for PubMedID 9228090

  • RNA CLEAVAGE AND CHAIN ELONGATION BY ESCHERICHIA-COLI DNA-DEPENDENT RNA-POLYMERASE IN A BINARY ENZYME RNA COMPLEX PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Altmann, C. R., SOLOWCORDERO, D. E., Chamberlin, M. J. 1994; 91 (9): 3784-3788

    Abstract

    In the absence of DNA, Escherichia coli RNA polymerase (EC 2.7.7.6) can bind RNA to form an equimolar binary complex with the concomitant release of the sigma factor. We show now that E. coli RNA polymerase binds at a region near the 3' terminus of the RNA and that an RNA in such RNA.RNA polymerase complexes undergoes reactions previously thought to be unique to nascent RNA in ternary complexes with DNA. These include GreA/GreB-dependent cleavage of the RNA and elongation by 3'-terminal addition of NMP from NTP. Both of these reactions are inhibited by rifampicin. Hence, by several criteria, the RNA in binary complexes is bound to the polymerase in a manner quite similar to that in ternary complexes. These findings can be explained by a model for the RNA polymerase ternary complex in which the RNA is bound at the 3' terminus through two protein binding sites located up to 10 nt apart. In this model, the stability of RNA binding to the polymerase in the ternary complex is due primarily to its interaction with the protein.

    View details for Web of Science ID A1994NJ03400065

    View details for PubMedID 7513426

  • A C-TERMINAL DELETION IN CORYNEBACTERIUM-GLUTAMICUM HOMOSERINE DEHYDROGENASE ABOLISHES ALLOSTERIC INHIBITION BY L-THREONINE GENE Archer, J. A., SOLOWCORDERO, D. E., Sinskey, A. J. 1991; 107 (1): 53-59

    Abstract

    In Escherichia coli, Bacillus subtilis and Corynebacterium glutamicum, homoserine dehydrogenase (HD), the enzyme after the branch point of the threonine/methionine and lysine biosynthetic pathways, is allosterically inhibited by L-threonine. To investigate the regulation of the C. glutamicum HD enzyme by L-threonine, the structural gene, hom, was mutated by UV irradiation of whole cells to obtain a deregulated allele, homdr. L-Threonine inhibits the wild-type (wt) enzyme with a Ki of 0.16 mM. The deregulated enzyme remains 80% active in the presence of 50 mM L-threonine. The homdr gene mutant was isolated and cloned in E. coli. In a C. glutamicum wt host background, but not in E. coli, the cloned homdr gene is genetically unstable. The cloned homdr gene is overexpressed tenfold in C. glutamicum and is active in the presence of over 60 mM L-threonine. Sequence analysis revealed that the homdr mutation is a single nucleotide (G1964) deletion in codon 429 within the hom reading frame. The resulting frame-shift mutation radically alters the structure of the C terminus, resulting in ten amino acid (aa) changes and a deletion of the last 7 aa relative to the wt protein. These observations suggest that the C terminus may be associated with the L-threonine allosteric response. The homdr mutation is unstable and probably deleterious to the cell. This may explain why only one mutation was obtained despite repeated mutagenesis.

    View details for Web of Science ID A1991GU00800007

    View details for PubMedID 1743520

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