COMPARE Analysis, a Bioinformatic Approach to Accelerate Drug Repurposing against Covid-19 and Other Emerging Epidemics

SLAS DISCOVERY Advancing Life Sciences ◽

10.1177/2472555220975672 ◽

2020 ◽

pp. 247255522097567

Author(s):

Imad Naasani

Keyword(s):

Human Cancer ◽

Drug Repurposing ◽

Data Repository ◽

Human Cancer Cell Lines ◽

Chemical Structures ◽

Drug Molecules ◽

Growth Inhibitory ◽

Antiviral Activities ◽

Bioinformatic Approach ◽

Compare Analysis

A novel bioinformatic approach for drug repurposing against emerging viral epidemics like Covid-19 is described. It exploits the COMPARE algorithm, a public program from the National Cancer Institute (NCI) to sort drugs according to their patterns of growth inhibitory profiles from a diverse panel of human cancer cell lines. The data repository of the NCI includes the growth inhibitory patterns of more than 55,000 molecules. When candidate drug molecules with ostensible anti-SARS-CoV-2 activities were used as seeds (e.g., hydroxychloroquine, ritonavir, and dexamethasone) in COMPARE, the analysis uncovered several molecules with fingerprints similar to the seeded drugs. Interestingly, despite the fact that the uncovered drugs were from various pharmacological classes (antiarrhythmic, nucleosides, antipsychotic, alkaloids, antibiotics, and vitamins), they were all reportedly known from published literature to exert antiviral activities via different modes, confirming that COMPARE analysis is efficient for predicting antiviral activities of drugs from various pharmacological classes. Noticeably, several of the uncovered drugs can be readily tested, like didanosine, methotrexate, vitamin A, nicotinamide, valproic acid, uridine, and flucloxacillin. Unlike pure in silico methods, this approach is biologically more relevant and able to pharmacologically correlate compounds regardless of their chemical structures. This is an untapped resource, reliable and readily exploitable for drug repurposing against current and future viral outbreaks.

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Synthesis of quaternary 8-(1-acylethene-1-yl)-13-methylcoptisine chlorides and their selective growth inhibitory activity between human cancer cell lines and normal intestinal epithelial cell-6

Chinese Chemical Letters ◽

10.1016/j.cclet.2017.08.026 ◽

2018 ◽

Vol 29 (1) ◽

pp. 131-135 ◽

Cited By ~ 1

Author(s):

Zhi-Hui Zhang ◽

Yu Yan ◽

An-Jun Deng ◽

Hai-Jing Zhang ◽

Zhi-Hong Li ◽

...

Keyword(s):

Epithelial Cell ◽

Cell Lines ◽

Inhibitory Activity ◽

Intestinal Epithelial Cell ◽

Human Cancer ◽

Intestinal Epithelial ◽

Human Cancer Cell ◽

Human Cancer Cell Lines ◽

Growth Inhibitory ◽

Growth Inhibitory Activity

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Cytotoxic Polyketides from the Marine Sponge-Derived Fungus Pestalotiopsis heterocornis XWS03F09

Molecules ◽

10.3390/molecules24142655 ◽

2019 ◽

Vol 24 (14) ◽

pp. 2655 ◽

Cited By ~ 2

Author(s):

Lei ◽

Zhou ◽

Hu ◽

Niu ◽

...

Keyword(s):

Marine Sponge ◽

Spectroscopic Analysis ◽

Fermentation Broth ◽

Human Cancer ◽

Optical Rotation ◽

Cytotoxic Activities ◽

Human Cancer Cell Lines ◽

Chemical Structures ◽

Ic50 Values ◽

New Compounds

Four new compounds, including two new polyketides, heterocornols M and N (1, 2), and a pair of epimers, heterocornols O and P (3, 4), were isolated from the fermentation broth of the marine sponge-derived fungus Pestalotiopsis heterocornis XWS03F09, together with three known compounds (5–7). The new chemical structures were established on the basis of a spectroscopic analysis, optical rotation, experimental and calculated electronic circular dichroism (ECD). All of the compounds (1–7) were evaluated for their cytotoxic activities, and heterocornols M-P (1–4) exhibited cytotoxicities against four human cancer cell lines with IC50 values of 20.4–94.2 μM.

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Bioactive Components of Fissistigma cupreonitens

Natural Product Communications ◽

10.1177/1934578x1801300607 ◽

2018 ◽

Vol 13 (6) ◽

pp. 1934578X1801300 ◽

Cited By ~ 1

Author(s):

I-Hsiao Chen ◽

Ming-Yi Yang ◽

Shin-Hun Juang ◽

Chia-Lin Lee ◽

Tran-Dinh Thang ◽

...

Keyword(s):

Cell Line ◽

Human Cancer ◽

Spectroscopic Methods ◽

Human Cancer Cell ◽

Bioactive Components ◽

Standard Drug ◽

Human Cancer Cell Lines ◽

Chemical Structures ◽

Phytochemical Investigation ◽

First Time

Phytochemical investigation of Fissistigma cupreonitens (Annonaceae) led to the isolation of 34 compounds. The chemical structures of all compounds were determined by spectroscopic methods. Among the isolates, compounds 20–27 and 31–34 were reported from this genus for the first time. From the results of the cytotoxicity assay against three human cancer cell lines (NCI-H226, NPC-TW01, and Jurkat E6–1), oxoaporphine compounds oxoxylopine (1), oxocrebanine (3), kuafumine (4) and lysicamine (5), and the flavonoid adunctin E (26) displayed significant cytotoxicity against NCI-H226 cell line, with IC50 values of 8.45, 8.10, 8.54, 12.83 and 12.00 μM, respectively, in comparison with the standard drug, cisplatin with IC50 of 13.37 μM.

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Synthesis of C4-fluorinated solamins and their growth inhibitory activity against human cancer cell lines

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2008.10.069 ◽

2008 ◽

Vol 18 (24) ◽

pp. 6451-6453 ◽

Cited By ~ 9

Author(s):

Naoto Kojima ◽

Hiromi Hayashi ◽

Satoshi Suzuki ◽

Hiroaki Tominaga ◽

Naoyoshi Maezaki ◽

...

Keyword(s):

Cell Lines ◽

Cancer Cell ◽

Inhibitory Activity ◽

Human Cancer ◽

Cancer Cell Lines ◽

Human Cancer Cell ◽

Human Cancer Cell Lines ◽

Growth Inhibitory ◽

Growth Inhibitory Activity

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ChemInform Abstract: Design and Synthesis of C35-Fluorinated Solamins and Their Growth Inhibitory Activities Against Human Cancer Cell Lines.

ChemInform ◽

10.1002/chin.201209220 ◽

2012 ◽

Vol 43 (9) ◽

pp. no-no

Author(s):

Naoto Kojima ◽

Yuki Suga ◽

Hiromi Hayashi ◽

Takao Yamori ◽

Takehiko Yoshimitsu ◽

...

Keyword(s):

Cell Lines ◽

Cancer Cell ◽

Human Cancer ◽

Cancer Cell Lines ◽

Human Cancer Cell ◽

Human Cancer Cell Lines ◽

Design And Synthesis ◽

Growth Inhibitory ◽

Inhibitory Activities

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Functional linkage of gene fusions to cancer cell fitness assessed by pharmacological and CRISPR/Cas9 screening

10.1101/559690 ◽

2019 ◽

Author(s):

Gabriele Picco ◽

Elisabeth D Chen ◽

Luz Garcia Alonso ◽

Fiona M Behan ◽

Emanuel Gonçalves ◽

...

Keyword(s):

Tumor Cell ◽

Cancer Cell ◽

Human Cancer ◽

Drug Repurposing ◽

Gene Fusions ◽

Sequencing Data ◽

Multiple Cancer ◽

Driver Genes ◽

Systematic Analysis ◽

Human Cancer Cell Lines

AbstractMany gene fusions have been reported in tumours and for most their role remains unknown. As fusions can be used clinically for diagnostic and prognostic purposes, and are targets for treatment, it is crucial to assess their functional implications in cancer. To investigate the role of fusions in tumor cell fitness, we developed a systematic analysis utilising RNA-sequencing data from 1,011 human cancer cell lines to functionally link 8,354 gene fusion events with genomic data, sensitivity to >350 anti-cancer drugs and CRISPR-Cas9 loss-of-fitness information. Established clinically-relevant fusions were readily identified. Overall, functional fusions were rare, including those involving cancer driver genes, suggesting that many fusions are dispensable for tumor cell fitness. Novel therapeutically actionable fusions involving RAF1, BRD4 and ROS1 were verified in new histologies. In addition, recurrent YAP1-MAML2 fusions were identified as activators of Hippo-pathway signaling in multiple cancer types, supporting therapeutic targeting of Hippo signalling. Our approach discriminates functional fusions, identifying new drivers of carcinogenesis and fusions that could have important clinical implications.SignificanceWe identify fusions as new potential candidates for drug repurposing and drivers of carcinogenesis. These results support histology agnostic marker-driven precision cancer medicine. Most fusions are not functional with implications for interpreting cancer fusions reported from clinical sequencing studies.

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Discovery of Potent Covid-19 Main Protease Inhibitors Using Machine Learning Based Virtual Screening Strategy

10.26434/chemrxiv.12090423.v1 ◽

2020 ◽

Author(s):

Muthu Kumar T ◽

Rohini K ◽

Nivya James ◽

Shanthi V ◽

Ramanathan Karuppasamy

Keyword(s):

Machine Learning ◽

Binding Free Energy ◽

Drug Repurposing ◽

Screening Strategy ◽

Antiviral Therapies ◽

Drug Molecules ◽

Main Protease ◽

Antiviral Activities ◽

Imminent Threat ◽

Potential Inhibitors

<p>The emergence and rapid spreading of novel SARS-CoV-2 across the globe represent an imminent threat to public health. Novel antiviral therapies are urgently needed to overcome this pandemic. Given the great role of main protease of Covid-19 for virus replication, we performed drug repurposing study using recently deposited main protease structure, 6LU7. For instance, pharmacophore- and e-pharmacophore-based hypotheses such as AARRH and AARR respectively were developed using available small molecule inhibitors and utilized in the screening of DrugBank repository. Further, hierarchical docking protocol was implemented with the support of Glide algorithm. The resultant compounds were then examined for its binding free energy against main protease of Covid-19 by means of Prime-MM/GBSA algorithm. Most importantly, the resultant compounds antiviral activities were further predicted by machine learning-based model generated by AutoQSAR algorithm. Finally, the hit molecules were examined for its drug likeness and its toxicity parameters through QikProp algorithm. Overall, the present analysis yielded four potential inhibitors (DB07800, DB08573, DB03744 and DB02986) that are predicted to bind with main protease of Covid-19 better than currently used drug molecules such as N3 (co-crystallized native ligand), Lopinavir and Ritonavir. </p>

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Naphthalene substituted benzo[c]coumarins: Synthesis, characterization and evaluation of antibacterial activity and cytotoxicity

Heterocyclic Communications ◽

10.1515/hc-2019-0024 ◽

2019 ◽

Vol 25 (1) ◽

pp. 146-151

Author(s):

Mrugesh Patel ◽

Kaushal Patel

Keyword(s):

Antibacterial Activity ◽

Cell Lines ◽

Cancer Cell ◽

Human Cancer ◽

Cancer Cell Lines ◽

Spectroscopic Techniques ◽

Cell Viability Assay ◽

Human Cancer Cell Lines ◽

Significant Growth ◽

Growth Inhibitory

AbstractNovel congeners of naphthalene substituted benzo[c]coumarins (2a-f) were synthesized by reaction of various 3-coumarinoyl methyl pyridinium bromide salts (1a-d) with a selected set of acetyl naphthalene in the presence of sodium acetate in refluxing glacial acetic acid. Structures of the synthesized compounds were confirmed by elemental analysis and by various spectroscopic techniques such as 1H-NMR, 13C-NMR, DEPT, and MS spectral data. Synthesised compounds were screened for antibacterial activity and cytotoxicity against different human cancer cell lines including cervix cancer (HeLa), breast cancer (MCF-7) and lung cancer (A549) using tetrazolium dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell viability assay. Although with varying degrees, a significant growth inhibitory and cytotoxic effects were observed on all three cancer cell lines. Compounds 2b and 2e showed significant growth inhibitory and cytotoxicity against aforementioned cancer cell lines.

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Strategies To Identify Effective Treatments For Proteasome Inhibitor Resistant Multiple Myeloma

Blood ◽

10.1182/blood.v122.21.278.278 ◽

2013 ◽

Vol 122 (21) ◽

pp. 278-278

Author(s):

Brian Van Ness ◽

Holly A. F. Stessman ◽

Linda B. Baughn ◽

Aatif Mansoor ◽

Amit Mitra ◽

...

Keyword(s):

Data Base ◽

Cell Lines ◽

Research Funding ◽

Human Cancer ◽

Expression Profiles ◽

Single Agent ◽

Cross Resistance ◽

Human Cancer Cell Lines ◽

Chemical Structures

Abstract Despite the introduction of effective new agents in the treatment of myeloma, the disease is still mostly incurable. Among the most significant issues is the heterogeneity of the disease, with accumulation of multiple genetic abnormalities among patients, resulting in disease refractory to some highly active agents, or the emergence of resistance leading to aggressive relapse. We have focused efforts on modeling drug sensitivity, and generating both genetic and biomarker signatures of response and resistance to the proteasome inhibitors (PIs): bortezomib (Btz), MLN2238 (Takeda) and carfilzomob (Onyx). Using mouse and human myeloma cell lines we dose escalated with bortezomib and selected bortezomib-resistant (Btz-R) lines (that showed cross resistance to MLN2238 and carfilzomib). We previously reported the identification of gene expression signatures that distinguish sensitivity or resistance to bortezomib (Stessman, et al., Mol Cancer Ther 12:1140, 2013). We then took three approaches to identify effective strategies to treat bortezomib resistance: 1) The connectivity map (CMAP) data base contains treatment induced transcriptional signatures from over 1300 bioactive compounds in human cancer cell lines. We queried our Btz-R expression profiles against the CMAP data base and developed a correlation analysis to identify potential drugs that would be predicted to show toxicity to Btz-R lines. We identified HDAC-inhibitor and topoisomerase-inhibitor sensitivity profiles that were able to predict Btz-R tumor responsiveness to these drugs in vitro. 2) We found that Btz-R was associated with loss of PC maturation markers (CD69, CD93, BLIMP, CXCR4, spliced XBP-1), and were able to re-sensitize Btz-R cells to Btz sensitivity by inducing PC maturation. The correlation of expression markers we identified stratified survival outcomes in bortezomib containing clinical trials; thus demonstrating the markers we identified in the in vitro modeling are relevant to patient outcomes. 3) Finally, we designed a cell-based high throughput drug screening approach that led to the identification of several chemical structures with selective activity against Btz-R cells. Topoisomerase-inhibitors were among the top hits, a finding that independently supported our CMAP screening results. We also identified a more novel chemical lead (Velcade Re-sensitizing Compound 2; VRC-2) that showed modest but significant selectivity for Btz-R cells as a single agent, and most notably, exhibited potent Btz re-sensitizing activity when the 2 drugs were combined. The Btz re-sensitizing activity of VRC-2 was confirmed using multiple human and mouse Btz-R cell lines. The initial successes of the in vitro approaches that will be presented demonstrate the value of profiling resistant tumors as a means to identify secondary therapies, and demonstrate there are powerful screening approaches that can be used to effectively treat or reverse drug resistance. Disclosures: Van Ness: Millenium Pharnaceutical: Honoraria, Research Funding; Onyx Pharmaceutical: Research Funding.

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