David Solow-Cordero

All Publications

• Repurposing mebendazole against triple-negative breast cancer CNS metastasis. Journal of neuro-oncology Rodrigues, A. J., Chernikova, S. B., Wang, Y., Trinh, T. T., Solow-Cordero, D. E., Alexandrova, L., Casey, K. M., Alli, E., Aggarwal, A., Quill, T., Koegel, A. K., Feldman, B. J., Ford, J. M., Hayden-Gephart, M. 2024

  Abstract

  PURPOSE: Triple-negative breast cancer (TNBC) often metastasizes to the central nervous system (CNS) and has the highest propensity among breast cancer subtypes to develop leptomeningeal disease (LMD). LMD is a spread of cancer into leptomeningeal space that speeds up the disease progression and severely aggravates the prognosis. LMD has limited treatment options. We sought to test whether the common anti-helminthic drug mebendazole (MBZ) may be effective against murine TNBC LMD.METHODS: A small-molecule screen involving TNBC cell lines identified benzimidazoles as potential therapeutic agents for further study. In vitro migration assays were used to evaluate cell migration capacity and the effect of MBZ. For in vivo testing, CNS metastasis was introduced into BALB/c athymic nude mice through internal carotid artery injections of brain-tropic MDA-MB-231-BR or MCF7-BR cells. Tumor growth and spread was monitored by bioluminescence imaging and immunohistochemistry. MBZ was given orally at 50 and 100mg/kg doses. MBZ bioavailability was assayed by mass spectrometry.RESULTS: Bioinformatic analysis and migration assays revealed higher migratory capacity of TNBC compared to other breast cancer subtypes. MBZ effectively slowed down migration of TNBC cell line MDA-MB-231 and its brain tropic derivative MDA-MB-231-BR. In animal studies, MBZ reduced leptomeningeal spread, and extended survival in brain metastasis model produced by MDA-MB-231-BR cells. MBZ did not have an effect in the non-migratory MCF7-BR model.CONCLUSIONS: We demonstrated that MBZ is a safe and effective oral agent in an animal model of TNBC CNS metastasis. Our findings are concordant with previous efforts involving MBZ and CNS pathology and support the drug's potential utility to slow down leptomeningeal spread.

  View details for DOI 10.1007/s11060-024-04654-x

  View details for PubMedID 38563850

• Anticancer pan-ErbB inhibitors reduce inflammation and tissue injury and exert broad-spectrum antiviral effects. The Journal of clinical investigation Saul, S., Karim, M., Ghita, L., Huang, P. T., Chiu, W., Durán, V., Lo, C. W., Kumar, S., Bhalla, N., Leyssen, P., Alem, F., Boghdeh, N. A., Tran, D. H., Cohen, C. A., Brown, J. A., Huie, K. E., Tindle, C., Sibai, M., Ye, C., Khalil, A. M., Chiem, K., Martinez-Sobrido, L., Dye, J. M., Pinsky, B. A., Ghosh, P., Das, S., Solow-Cordero, D. E., Jin, J., Wikswo, J. P., Jochmans, D., Neyts, J., De Jonghe, S., Narayanan, A., Einav, S. 2023

  Abstract

  Targeting host factors exploited by multiple viruses could offer broad-spectrum solutions for pandemic preparedness. Seventeen candidates targeting diverse functions emerged in a screen of 4,413 compounds for SARS-CoV-2 inhibitors. We demonstrated that lapatinib and other approved inhibitors of the ErbB family receptor tyrosine kinases suppress replication of SARS-CoV-2, Venezuelan equine encephalitis virus (VEEV), and other emerging viruses with a high barrier to resistance. Lapatinib suppressed SARS-CoV-2 entry and later stages of the viral life cycle and showed synergistic effect with the direct-acting antiviral nirmatrelvir. We discovered that ErbB1, 2 and 4 bind SARS-CoV-2 S1 protein and regulate viral and ACE2 internalization, and they are required for VEEV infection. In human lung organoids, lapatinib protected from SARS-CoV-2-induced activation of ErbB-regulated pathways implicated in non-infectious lung injury, pro-inflammatory cytokine production, and epithelial barrier injury. Lapatinib suppressed VEEV replication, cytokine production and disruption of the blood-brain barrier integrity in microfluidic-based human neurovascular units, and reduced mortality in a lethal infection murine model. We validated lapatinib-mediated inhibition of ErbB activity as an important mechanism of antiviral action. These findings reveal regulation of viral replication, inflammation, and tissue injury via ErbBs and establish a proof-of-principle for a repurposed, ErbB-targeted approach to combat emerging viruses.

  View details for DOI 10.1172/JCI169510

  View details for PubMedID 37581931

• Maprotiline restores ER homeostasis and rescues neurodegeneration via Histamine Receptor H1 inhibition in retinal ganglion cells. Nature communications Chen, W., Liu, P., Liu, D., Huang, H., Feng, X., Fang, F., Li, L., Wu, J., Liu, L., Solow-Cordero, D. E., Hu, Y. 2022; 13 (1): 6796

  Abstract

  When the protein or calcium homeostasis of the endoplasmic reticulum (ER) is adversely altered, cells experience ER stress that leads to various diseases including neurodegeneration. Genetic deletion of an ER stress downstream effector, CHOP, significantly protects neuron somata and axons. Here we report that three tricyclic compounds identified through a small-scale high throughput screening using a CHOP promoter-driven luciferase cell-based assay, effectively inhibit ER stress by antagonizing their common target, histamine receptor H1 (HRH1). We further demonstrated that systemic administration of one of these compounds, maprotiline, or CRISPR-mediated retinal ganglion cell (RGC)-specific HRH1 inhibition, delivers considerable neuroprotection of both RGC somata and axons and preservation of visual function in two mouse optic neuropathy models. Finally, we determine that maprotiline restores ER homeostasis by inhibiting HRH1-mediated Ca2+ release from ER. In this work we establish maprotiline as a candidate neuroprotectant and HRH1 as a potential therapeutic target for glaucoma.

  View details for DOI 10.1038/s41467-022-34682-y

  View details for PubMedID 36357388

• Targeting RTN4/NoGo-Receptor reduces levels of ALS protein ataxin-2. Cell reports Rodriguez, C. M., Bechek, S. C., Jones, G. L., Nakayama, L., Akiyama, T., Kim, G., Solow-Cordero, D. E., Strittmatter, S. M., Gitler, A. D. 2022; 41 (4): 111505

  Abstract

  Gene-based therapeutic strategies to lower ataxin-2 levels are emerging for the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia type 2 (SCA2). Additional strategies to lower levels of ataxin-2 could be beneficial. Here, we perform a genome-wide arrayed small interfering RNA (siRNA) screen in human cells and identify RTN4R, the gene encoding the RTN4/NoGo-Receptor, as a potent modifier of ataxin-2 levels. RTN4R knockdown, or treatment with a peptide inhibitor, is sufficient to lower ataxin-2 protein levels in mouse and human neurons in vitro, and Rtn4r knockout mice have reduced ataxin-2 levels in vivo. We provide evidence that ataxin-2 shares a role with the RTN4/NoGo-Receptor in limiting axonal regeneration. Reduction of either protein increases axonal regrowth following axotomy. These data define the RTN4/NoGo-Receptor as a novel therapeutic target for ALS and SCA2 and implicate the targeting of ataxin-2 as a potential treatment following nerve injury.

  View details for DOI 10.1016/j.celrep.2022.111505

  View details for PubMedID 36288715

• Casein kinase 2 inhibition sensitizes medulloblastoma to temozolomide. Oncogene Nitta, R. T., Bolin, S. n., Luo, E. n., Solow-Codero, D. E., Samghabadi, P. n., Purzner, T. n., Aujla, P. S., Nwagbo, G. n., Cho, Y. J., Li, G. n. 2019

  Abstract

  Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Since surviving patients experience severe neurocognitive disabilities, better and more effective treatments are needed to enhance their quality of life. Casein kinase 2 (CK2) is known to regulate cell growth and survival in multiple cancers; however, the role of CK2 in MB is currently being studied. In this study, we verified the importance of CK2 in MB tumorigenesis and discovered that inhibition of CK2 using the small molecule inhibitor, CX-4945, can sensitize MB cells to a well-known and tolerated chemotherapeutic, temozolomide (TMZ). To study the role of CK2 in MB we modulated CK2 expression in multiple MB cells. Exogenous expression of CK2 enhanced cell growth and tumor growth in mice, while depletion or inhibition of CK2 expression decreased MB tumorigenesis. Treatment with CX-4945 reduced MB growth and increased apoptosis. We conducted a high-throughput screen where 4000 small molecule compounds were analyzed to identify compounds that increased the anti-tumorigenic properties of CX-4945. TMZ was found to work synergistically with CX-4945 to decrease cell survival and increase apoptosis in MB cells. O-6-methylguanine-DNA methyltransferase (MGMT) activity is directly correlated to TMZ sensitivity. We found that loss of CK2 activity reduced β-catenin expression, a known MGMT regulator, which in turn led to a decrease in MGMT expression and an increased sensitivity to TMZ. Our findings show that CK2 is important for MB maintenance and that treatment with CX-4945 can sensitize MB cells to TMZ treatment.

  View details for DOI 10.1038/s41388-019-0927-y

  View details for PubMedID 31406250

• Correction: Casein kinase 2 inhibition sensitizes medulloblastoma to temozolomide. Oncogene Nitta, R. T., Bolin, S. n., Luo, E. n., Solow-Cordero, D. E., Samghabadi, P. n., Purzner, T. n., Aujla, P. S., Nwagbo, G. n., Cho, Y. J., Li, G. n. 2019

  Abstract

  The original version of this Article contained an error in the spelling of the author David Solow-Cordero, which was incorrectly given as David Solow-Codero. This has now been corrected in both the PDF and HTML versions of the Article.

  View details for DOI 10.1038/s41388-019-1077-y

  View details for PubMedID 31659253

• A high-throughput system to identify inhibitors of Candidatus Liberibacter asiaticus transcription regulators. Proceedings of the National Academy of Sciences of the United States of America Barnett, M. J., Solow-Cordero, D. E., Long, S. R. 2019

  Abstract

  Citrus greening disease, also known as huanglongbing (HLB), is the most devastating disease of Citrus worldwide. This incurable disease is caused primarily by the bacterium Candidatus Liberibacter asiaticus and spread by feeding of the Asian Citrus Psyllid, Diaphorina citriCa L. asiaticus cannot be cultured; its growth is restricted to citrus phloem and the psyllid insect. Management of infected trees includes use of broad-spectrum antibiotics, which have disadvantages. Recent work has sought to identify small molecules that inhibit Ca L. asiaticus transcription regulators, based on a premise that at least some regulators control expression of genes necessary for virulence. We describe a synthetic, high-throughput screening system to identify compounds that inhibit activity of Ca L. asiaticus transcription activators LdtR, RpoH, and VisNR. Our system uses the closely related model bacterium, Sinorhizobium meliloti, as a heterologous host for expression of a Ca L. asiaticus transcription activator, the activity of which is detected through expression of an enhanced green fluorescent protein (EGFP) gene fused to a target promoter. We used this system to screen more than 120,000 compounds for compounds that inhibited regulator activity, but not growth. Our screen identified several dozen compounds that inhibit regulator activity in our assay. This work shows that, in addition to providing a means of characterizing Ca L. asiaticus regulators, an S. meliloti host can be used for preliminary identification of candidate inhibitory molecules.

  View details for DOI 10.1073/pnas.1905149116

  View details for PubMedID 31427509

• High-Throughput Screening of Entamoeba Identifies Compounds Which Target Both Life Cycle Stages and Which Are Effective Against Metronidazole Resistant Parasites. Frontiers in cellular and infection microbiology Ehrenkaufer, G. M., Suresh, S., Solow-Cordero, D., Singh, U. 2018; 8: 276

  Abstract

  Neglected tropical diseases, especially those caused by parasites, are significantly underserved by current drug development efforts, mostly due to the high costs and low economic returns. One method for lowering the costs of drug discovery and development for these diseases is to repurpose drugs developed for other indications. Here, we present the results of a screen of five repurposed drug libraries to identify potential new lead compounds to treat amebiasis, a disease that affects tens of millions of people and causes ~100,000 deaths annually. E. histolytica, the causative agent of amebiasis, has two major life cycle stages, the trophozoite and the cyst. The current primary treatment for amebiasis, nitroimidazole compounds, do not eliminate parasites from the colonic lumen, necessitating a multi-drug treatment regimen. We aimed to address this problem by screening against both life stages, with the aim of identifying a single drug that targets both. We successfully identified eleven compounds with activity against both cysts and trophozoites, as well as multiple compounds that killed trophozoites with improved efficacy over existing drugs. Two lead compounds (anisomycin and prodigiosin) were further characterized for activity against metronidazole (MNZ) resistant parasites and mature cysts. Anisomycin and prodigiosin were both able to kill MNZ resistant parasites while prodigiosin and its analog obatoclax were active against mature cysts. This work confirms the feasibility of identifying drugs that target both Entamoeba trophozoites and cysts, and is an important step toward developing improved treatment regimens for Entamoeba infection.

  View details for DOI 10.3389/fcimb.2018.00276

  View details for PubMedID 30175074

  View details for PubMedCentralID PMC6107840

• Fragile Histidine Triad (FHIT), a Novel Modifier Gene in Pulmonary Arterial Hypertension. American journal of respiratory and critical care medicine Dannewitz Prosseda, S., Tian, X., Kuramoto, K., Boehm, M., Sudheendra, D., Miyagawa, K., Zhang, F., Solow-Cordero, D., Saldivar, J. C., Austin, E. D., Loyd, J. E., Wheeler, L., Andruska, A., Donato, M., Wang, L., Huebner, K., Metzger, R. J., Khatri, P., Spiekerkoetter, E. 2018

  Abstract

  RATIONALE: Pulmonary arterial hypertension (PAH) is characterized by progressive narrowing of pulmonary arteries resulting in right heart failure and death. Bone Morphogenetic Protein Receptor type-2 (BMPR2) mutations account for most familial PAH (FPAH) forms while reduced BMPR2 is present in many idiopathic PAH (IPAH) forms, suggesting dysfunctional BMPR2 signaling to be a key feature of PAH. Modulating BMPR2 signaling is therapeutically promising, yet how BMPR2 is downregulated in PAH is unclear.OBJECTIVES: We intended to identify and pharmaceutically target BMPR2 modifier genes to improve PAH.METHODS: We combined siRNA High Throughput Screening (HTS) of >20,000 genes with a multi-cohort analysis of publicly available PAH RNA expression data to identify clinically relevant BMPR2-modifiers. After confirming gene dysregulation in PAH patient tissue, we determined the functional roles of BMPR2-modifiers in vitro and tested the repurposed drug Enzastaurin for its propensity to improve experimental PH.MEASUREMENTS AND MAIN RESULTS: We discovered Fragile Histidine Triad (FHIT) as a novel BMPR2-modifier. BMPR2 and FHIT expression were reduced in PAH patients. FHIT reductions were associated with endothelial and smooth muscle cell dysfunction, rescued by Enzastaurin through a dual mechanism: upregulation of FHIT as well as miR17-5 repression. Fhit-/- mice had exaggerated hypoxic PH and failed to recover in normoxia. Enzastaurin reversed PH in the Sugen5416/Hypoxia/Normoxia rat model, by improving Right Ventricular Systolic Pressure (RVSP), RV hypertrophy, cardiac fibrosis and vascular remodeling.CONCLUSIONS: This study highlights the importance of the novel BMPR2 modifier FHIT in PH and the clinical value of the repurposed drug Enzastaurin as a potential novel therapeutic strategy to improve PAH.

  View details for PubMedID 30107138

• A Human Genome-wide RNAi Screen Reveals Diverse Modulators that Mediate IRE1α-XBP1 Activation. Molecular cancer research : MCR Yang, Z. n., Zhang, J. n., Jiang, D. n., Khatri, P. n., Solow-Cordero, D. E., Toesca, D. A., Koumenis, C. n., Denko, N. C., Giaccia, A. J., Le, Q. T., Koong, A. C. 2018

  Abstract

  Activation of the unfolded protein response (UPR) signaling pathways is linked to multiple human diseases including cancer. The inositol-requiring kinase 1 (IRE1)-X-box binding protein 1 (XBP1) pathway is the most evolutionarily conserved of the three major signaling branches of the UPR. Here, we performed a genome-wide siRNA screen to obtain a systematic assessment of genes integrated in the IRE1-XBP1 axis. We monitored the expression of an XBP1-luciferase chimeric protein in which luciferase was fused in-frame with the spliced (active) form of XBP1. Using cells expressing this reporter construct, we identified 162 genes for which siRNA inhibition resulted in alteration in XBP1 splicing. These genes express diverse types of proteins modulating a wide range of cellular processes. Pathway analysis identified a set of genes implicated in the pathogenesis of breast cancer. Several genes including BCL10, GCLM, and IGF1R correlated with worse relapse-free survival (RFS) in an analysis of patients with triple negative breast cancer (TNBC). However, in this cohort of 1908 patients, only high GCLM expression correlated with worse RFS in both TNBC and non-TNBC patients. Altogether, our study revealed unidentified roles of novel pathways regulating the UPR and these findings may serve as a paradigm for exploring novel therapeutic opportunities based on modulating the UPR.Genome-wide RNAi screen identifies novel genes/pathways that modulate IRE1-XBP1 signaling in human tumor cells and leads to the development of improved therapeutic approaches targeting the UPR.

  View details for PubMedID 29440447

• Dynamin impacts homology-directed repair and breast cancer response to chemotherapy. The Journal of clinical investigation Chernikova, S. B., Nguyen, R. B., Truong, J. T., Mello, S. S., Stafford, J. H., Hay, M. P., Olson, A. n., Solow-Cordero, D. E., Wood, D. J., Henry, S. n., von Eyben, R. n., Deng, L. n., Gephart, M. H., Aroumougame, A. n., Wiese, C. n., Game, J. C., Győrffy, B. n., Brown, J. M. 2018

  Abstract

  After the initial responsiveness of triple-negative breast cancers (TNBCs) to chemotherapy, they often recur as chemotherapy-resistant tumors, and this has been associated with upregulated homology-directed repair (HDR). Thus, inhibitors of HDR could be a useful adjunct to chemotherapy treatment of these cancers. We performed a high-throughput chemical screen for inhibitors of HDR from which we obtained a number of hits that disrupted microtubule dynamics. We postulated that high levels of the target molecules of our screen in tumors would correlate with poor chemotherapy response. We found that inhibition or knockdown of dynamin 2 (DNM2), known for its role in endocytic cell trafficking and microtubule dynamics, impaired HDR and improved response to chemotherapy of cells and of tumors in mice. In a retrospective analysis, levels of DNM2 at the time of treatment strongly predicted chemotherapy outcome for estrogen receptor-negative and especially for TNBC patients. We propose that DNM2-associated DNA repair enzyme trafficking is important for HDR efficiency and is a powerful predictor of sensitivity to breast cancer chemotherapy and an important target for therapy.

  View details for PubMedID 30371505

• Screening of NCI-DTP library to identify new drug candidates for Borrelia burgdorferi. journal of antibiotics Pothineni, V. R., Wagh, D., Babar, M. M., Inayathullah, M., Watts, R. E., Kim, K., Parekh, M. B., Gurjarpadhye, A. A., Solow-Cordero, D., Tayebi, L., Rajadas, J. 2017; 70 (3): 308-312

  View details for DOI 10.1038/ja.2016.131

  View details for PubMedID 27826144

• Acridine Derivatives as Inhibitors of the IRE1a-XBP1 Pathway Are Cytotoxic to Human Multiple Myeloma. Molecular cancer therapeutics Jiang, D., Tam, A. B., Alagappan, M., Hay, M. P., Gupta, A., Kozak, M. M., Solow-Cordero, D. E., Lum, P. Y., Denko, N. C., Giaccia, A. J., Le, Q., Niwa, M., Koong, A. C. 2016; 15 (9): 2055-2065

  Abstract

  Using a luciferase reporter-based high throughput chemical library screen and topological data analysis (TDA), we identified N-acridine-9-yl-N',N'-dimethylpropane-1,3-diamine (DAPA) as a inhibitor of the IRE1α-XBP1 pathway of the unfolded protein response (UPR). We designed a collection of analogues based on the structure of DAPA to explore structure-activity relationships (SAR) and identified N9-(3-(dimethylamino)propyl)-N3,N3,N6,N6-tetramethylacridine-3,6,9-triamine (3,6-DMAD), with 3,6-dimethylamino substitution on the chromophore, as a potent inhibitor. 3,6-DMAD inhibited both IRE1α oligomerization and in vitro endoribonuclease (RNase) activity, while the other analogues only blocked IRE1α oligomerization. Consistent with the inhibition of IRE1α-mediated XBP1 splicing, which is critical for multiple myeloma (MM) cell survival, these analogues were cytotoxic to MM cell lines. Furthermore, 3,6-DMAD inhibited XBP1 splicing and the growth of MM tumor xenografts. Our study not only confirmed the utilization of topological data analysis in drug discovery but also identified a class of compounds with a unique mechanism of action as potent IRE1α-XBP1 inhibitors in the treatment of MM.

  View details for DOI 10.1158/1535-7163.MCT-15-1023

  View details for PubMedID 27307600

• Small molecule screen for inhibitors of expression from canonical CREB response element-containing promoters. Oncotarget Mitton, B., Hsu, K., Dutta, R., Tiu, B. C., Cox, N., McLure, K. G., Chae, H., Smith, M., Eklund, E. A., Solow-Cordero, D. E., Sakamoto, K. M. 2016; 7 (8): 8653-8662

  Abstract

  The transcription factor CREB (cAMP Response Element Binding Protein) is an important determinant in the growth of Acute Myeloid Leukemia (AML) cells. CREB overexpression increases AML cell growth by driving the expression of key regulators of apoptosis and the cell cycle. Conversely, CREB knockdown inhibits proliferation and survival of AML cells but not normal hematopoietic cells. Thus, CREB represents a promising drug target for the treatment of AML, which carries a poor prognosis. In this study, we performed a high-throughput small molecule screen to identify compounds that disrupt CREB function in AML cells. We screened ~114,000 candidate compounds from Stanford University's small molecule library, and identified 5 molecules that inhibit CREB function at micromolar concentrations, but are non-toxic to normal hematopoietic cells. This study suggests that targeting CREB function using small molecules could provide alternative approaches to treat AML.

  View details for DOI 10.18632/oncotarget.7085

  View details for PubMedID 26840025

  View details for PubMedCentralID PMC4890994

• Identification of new drug candidates against Borrelia burgdorferi using high-throughput screening DRUG DESIGN DEVELOPMENT AND THERAPY Pothineni, V. R., Wagh, D., Babar, M. M., Inayathullah, M., Solow-Cordero, D., Kim, K., Samineni, A. V., Parekh, M. B., Tayebi, L., Rajadas, J. 2016; 10: 1307-1322

  Abstract

  Lyme disease is the most common zoonotic bacterial disease in North America. It is estimated that >300,000 cases per annum are reported in USA alone. A total of 10%-20% of patients who have been treated with antibiotic therapy report the recrudescence of symptoms, such as muscle and joint pain, psychosocial and cognitive difficulties, and generalized fatigue. This condition is referred to as posttreatment Lyme disease syndrome. While there is no evidence for the presence of viable infectious organisms in individuals with posttreatment Lyme disease syndrome, some researchers found surviving Borrelia burgdorferi population in rodents and primates even after antibiotic treatment. Although such observations need more ratification, there is unmet need for developing the therapeutic agents that focus on removing the persisting bacterial form of B. burgdorferi in rodent and nonhuman primates. For this purpose, high-throughput screening was done using BacTiter-Glo assay for four compound libraries to identify candidates that stop the growth of B. burgdorferi in vitro. The four chemical libraries containing 4,366 compounds (80% Food and Drug Administration [FDA] approved) that were screened are Library of Pharmacologically Active Compounds (LOPAC1280), the National Institutes of Health Clinical Collection, the Microsource Spectrum, and the Biomol FDA. We subsequently identified 150 unique compounds, which inhibited >90% of B. burgdorferi growth at a concentration of <25 µM. These 150 unique compounds comprise many safe antibiotics, chemical compounds, and also small molecules from plant sources. Of the 150 unique compounds, 101 compounds are FDA approved. We selected the top 20 FDA-approved molecules based on safety and potency and studied their minimum inhibitory concentration and minimum bactericidal concentration. The promising safe FDA-approved candidates that show low minimum inhibitory concentration and minimum bactericidal concentration values can be chosen as lead molecules for further advanced studies.

  View details for DOI 10.2147/DDDT.S101486

  View details for Web of Science ID 000373575000001

  View details for PubMedID 27103785

  View details for PubMedCentralID PMC4827596

• A small-molecule antivirulence agent for treating Clostridium difficile infection. Science translational medicine Bender, K. O., Garland, M., Ferreyra, J. A., Hryckowian, A. J., Child, M. A., Puri, A. W., Solow-Cordero, D. E., Higginbottom, S. K., Segal, E., Banaei, N., Shen, A., Sonnenburg, J. L., Bogyo, M. 2015; 7 (306): 306ra148-?

  Abstract

  Clostridium difficile infection (CDI) is a worldwide health threat that is typically triggered by the use of broad-spectrum antibiotics, which disrupt the natural gut microbiota and allow this Gram-positive anaerobic pathogen to thrive. The increased incidence and severity of disease coupled with decreased response, high recurrence rates, and emergence of multiple antibiotic-resistant strains have created an urgent need for new therapies. We describe pharmacological targeting of the cysteine protease domain (CPD) within the C. difficile major virulence factor toxin B (TcdB). Through a targeted screen with an activity-based probe for this protease domain, we identified a number of potent CPD inhibitors, including one bioactive compound, ebselen, which is currently in human clinical trials for a clinically unrelated indication. This drug showed activity against both major virulence factors, TcdA and TcdB, in biochemical and cell-based studies. Treatment in a mouse model of CDI that closely resembles the human infection confirmed a therapeutic benefit in the form of reduced disease pathology in host tissues that correlated with inhibition of the release of the toxic glucosyltransferase domain (GTD). Our results show that this non-antibiotic drug can modulate the pathology of disease and therefore could potentially be developed as a therapeutic for the treatment of CDI.

  View details for DOI 10.1126/scitranslmed.aac9103

  View details for PubMedID 26400909

• Therapeutic targeting of BRCA1-mutated breast cancers with agents that activate DNA repair. Cancer research Alli, E., Solow-Cordero, D., Casey, S. C., Ford, J. M. 2014; 74 (21): 6205-6215

  Abstract

  Cancers due to germline mutations in the BRCA1 gene tend to lack targets for approved chemoprevention agents. This study aimed at a targeted chemoprevention strategy for BRCA1-associated malignancies. Mutant BRCA1 limits the base-excision DNA repair activity that addresses oxidative DNA damage, the accumulation of which heightens one's risk for cancer. Therefore, we conducted a high-throughput chemical screen to identify drug candidates that could attenuate the inhibitory effects of mutant BRCA1 on this repair activity, thereby describing a new class of DNA repair-activating chemopreventive agents. In the screen design, such drugs functioned by enhancing base-excision DNA repair of oxidative DNA damage in the presence of mutant BRCA1, with minimal cytotoxicity. We identified at least one new agent that decreased malignant properties associated with tumorigenesis, including anchorage-independent growth and tumor progression. This work offers a preclinical proof-of-concept for a wholly new approach to chemoprevention in carriers of BRCA1 mutations, as a strategy to reduce the prevalence of BRCA1-associated malignancy.

  View details for DOI 10.1158/0008-5472.CAN-14-1716

  View details for PubMedID 25217519

• 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. 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., ten Dijke, P., Rabinovitch, M. 2013; 123 (8): 3600-3613

  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 DOI 10.1172/JCI65592

  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 (α and β) play different roles in response to chemotherapy. To identify isoform-selective inhibitors of Hsp90(α/β)/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(α/β) 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(α/β)/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 Hsp90α/p23 as compared with Hsp90β/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(α/β)/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 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 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

  View details for PubMedCentralID PMC3056474

• 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

  View details for PubMedCentralID PMC2721821

• 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

  View details for PubMedCentralID PMC2772893

• 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

  View details for PubMedCentralID PMC4154800

• 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