scholarly journals An Exon Skipping Screen Identifies Antitumor Drugs That Are Potent Modulators of Pre-mRNA Splicing, Suggesting New Therapeutic Applications

2019 ◽  
Author(s):  
Yihui Shi ◽  
Walter Bray ◽  
Alexander J. Smith ◽  
Wei Zhou ◽  
Joy Calaoagan ◽  
...  
Keyword(s):  
Small Molecule ◽  
Exon Skipping ◽  
Mrna Splicing ◽  
Luciferase Reporter ◽  
Antitumor Drugs ◽  
Small Molecule Ligands ◽  
A Cell ◽  
Displacement Assay ◽  
Approved Drugs ◽  
Fda Approved Drugs

ABSTRACTAgents that modulate pre-mRNA splicing are of interest in multiple therapeutic areas, including cancer. We report our recent screening results with the application of a cell-based Triple Exon Skipping Luciferase Reporter (TESLR) using a library that is composed of FDA approved drugs, clinical compounds, and mechanistically characterized tool compounds. Confirmatory assays showed that three clinical antitumor therapeutic candidates (milciclib, PF-3758309 and PF-030871) are potent splicing modulators and that these drugs are, in fact, nanomolar inhibitors of multiple kinases involved in the regulation the spliceosome. We also report the identification of new SF3B1 antagonists (sudemycinol C and E) and show that these antagonists can be used to develop a displacement assay for SF3B1 small molecule ligands. These results further supports the broad potential for the development of agents that target the spliceosome for the treatment of cancer and other diseases, as well as new avenues for chemotherapeutic discovery.

Small-molecule kinase inhibitors: an analysis of FDA-approved drugs

2016 ◽  
Vol 21 (1) ◽  
pp. 5-10 ◽  
Author(s):  
Peng Wu ◽  
Thomas E. Nielsen ◽  
Mads H. Clausen
Keyword(s):  
Small Molecule ◽  
Kinase Inhibitors ◽  
Approved Drugs ◽  
Fda Approved Drugs

Photoaffinity Labelling Strategies for Mapping the Small Molecule-Protein Interactome

2021 ◽  
Author(s):  
Nikolas R Burton ◽  
Phillip Kim ◽  
Keriann M. Backus
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Atomic Level ◽  
Photoaffinity Labelling ◽  
Protein Interactome ◽  
Approved Drugs ◽  
Fda Approved Drugs

Nearly all FDA approved drugs and bioactive small molecules exert their effects by binding to and modulating proteins. Consequently, understanding how small molecules interact with proteins at an atomic level...

scholarly journals Variable dose analysis: A novel RNAi-based method for detection of synthetic lethal interactions

2017 ◽  
Author(s):  
Benjamin E. Housden ◽  
Zhongchi Li ◽  
Colleen Kelley ◽  
Yuanli Wang ◽  
Yanhui Hu ◽  
...  
Keyword(s):  
Drug Targets ◽  
Limited Range ◽  
Synthetic Lethal ◽  
Candidate Drug ◽  
Highly Sensitive ◽  
Synthetic Lethal Interactions ◽  
A Cell ◽  
Approved Drugs ◽  
Fda Approved Drugs ◽  
Variable Dose

AbstractSynthetic sick or synthetic lethal (SS/L) screens are a powerful way to identify candidate drug targets to specifically kill tumor cells but such screens generally suffer from low reproducibility. We found that many SS/L interactions involve essential genes and are therefore detectable within a limited range of knockdown efficiency. Such interactions are often missed by overly efficient RNAi reagents. We therefore developed an assay that measures viability over a range of knockdown efficiency within a cell population. This method, called variable dose analysis (VDA), is highly sensitive to viability phenotypes and reproducibly detects SS/L interactions. We applied the VDA method to search for SS/L interactions with TSC1 and TSC2, the two tumor suppressors underlying tuberous sclerosis complex (TSC) and generated a SS/L network for TSC. Using this network, we identified four FDA-approved drugs that selectively affect viability of TSC deficient cells, representing promising candidates for repurposing to treat TSC-related tumors.

scholarly journals In silico and in vitro screening of FDA-approved drugs for potential repurposing against tuberculosis

2017 ◽  
Author(s):  
Sridharan Brindha ◽  
Jagadish Chandrabose Sundaramurthi ◽  
Savariar Vincent ◽  
Devadasan Velmurugan ◽  
John Joel Gnanadoss
Keyword(s):  
In Silico ◽  
Drug Targets ◽  
Luciferase Reporter ◽  
Synergistic Activity ◽  
Resistant Strains ◽  
Approved Drugs ◽  
Clinical Conditions ◽  
Drug Resistant Strains ◽  
Fda Approved Drugs

AbstractMotivationRepurposing of known drugs to newer clinical conditions is a promising avenue for finding novel therapeutic applications for tuberculosis.MethodsWe performed docking-based virtual screening for 1554 known drugs against two of the potential drug targets, namely trpD and coaA of M. tuberculosis. In the first round of in silico screening we used rigid docking using Glide and AutoDock Vina. We subjected the consistently ranked drugs for induced-fit docking by these tools against the same target proteins. We performed luciferase reporter phage (LRP) assay to determine the biological activity of five selected drugs against M. tuberculosis.ResultsWe observed lymecycline and cefpodoxime to be active against drug susceptible and drug resistant strains of M. tuberculosis. In addition, lymecycline and cefpodoxime showed synergistic activity with rifampin and isoniazid against M. tuberculosis.ConclusionOur results suggest that lymecycline and cefpodoxime have potential to be repurposed for the treatment of tuberculosis.

scholarly journals FDA-Approved Drugs for Hematological Malignancies—The Last Decade Review

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 87
Author(s):  
Aleksandra Sochacka-Ćwikła ◽  
Marcin Mączyński ◽  
Andrzej Regiec
Keyword(s):  
Small Molecule ◽  
Hematological Malignancies ◽  
European Medicines Agency ◽  
Car T Cells ◽  
Drug Conjugates ◽  
Car T ◽  
Recombinant Immunotoxins ◽  
Approved Drugs ◽  
Chemotherapy Agents ◽  
Fda Approved Drugs

Hematological malignancies, also referred to as blood cancers, are a group of diseases involving abnormal cell growth and persisting in the blood, lymph nodes, or bone marrow. The development of new targeted therapies including small molecule inhibitors, monoclonal antibodies, bispecific T cell engagers, antibody-drug conjugates, recombinant immunotoxins, and, finally, Chimeric Antigen Receptor T (CAR-T) cells has improved the clinical outcomes for blood cancers. In this review, we summarized 52 drugs that were divided into small molecule and macromolecule agents, approved by the Food and Drug Administration (FDA) in the period between 2011 and 2021 for the treatment of hematological malignancies. Forty of them have also been approved by the European Medicines Agency (EMA). We analyzed the FDA-approved drugs by investigating both their structures and mechanisms of action. It should be emphasized that the number of targeted drugs was significantly higher (46 drugs) than chemotherapy agents (6 drugs). We highlight recent advances in the design of drugs that are used to treat hematological malignancies, which make them more effective and less toxic.

scholarly journals An exon skipping screen identifies antitumor drugs that are potent modulators of pre-mRNA splicing, suggesting new therapeutic applications

PLoS ONE ◽  
2020 ◽  
Vol 15 (5) ◽  
pp. e0233672
Author(s):  
Yihui Shi ◽  
Walter Bray ◽  
Alexander J. Smith ◽  
Wei Zhou ◽  
Joy Calaoagan ◽  
...  
Keyword(s):  
Exon Skipping ◽  
Mrna Splicing ◽  
Antitumor Drugs ◽  
Therapeutic Applications

scholarly journals Combinatorial therapeutic plan for COVID-19 treatment armed up with antiviral, antiparasitic, cell-entry inhibitor, and immune-boosters

2020 ◽  
Author(s):  
Nabanita Roy Chattopadhyay ◽  
Koustav Chatterjee ◽  
Antara Banerjee ◽  
Tathagata Choudhuri
Keyword(s):  
Cell Entry ◽  
Entry Inhibitor ◽  
Time Loss ◽  
Antiparasitic Drug ◽  
A Cell ◽  
Host Cell Entry ◽  
Antiparasitic Drugs ◽  
Novel Coronavirus ◽  
Approved Drugs ◽  
Fda Approved Drugs

Abstract SARS-CoV-2, or novel coronavirus, is causing the fatal and contagious coronavirus disease-2019 (COVID-19) affecting thousands of people every single day. Researchers are continuously searching for any possible cure and/or vaccine, but no conclusive report is available till date. Like many others, we realize that a rapid, immediate, and elaborate strategy must be adopted to protect mankind. To avoid the time-loss due to clinical trials, we have tested some FDA-approved drugs to combat COVID-19. We accessed information from public databases and publications, and studied the mechanism of infection of SARS-CoV-2 and the interactions of various drugs with SARS-CoV-2 proteins in silico. We found a few antivirals and antiparasitic drugs to interact with important SARS-CoV-2 proteins. Particularly Galidesivir, Remdesivir, and Pirodavir are the chosen antiviral drugs; and Proguanil, Mefloquine, and Artesunate are the chosen antiparasitic drugs. In addition, inhibitors to prevent host-cell entry and a few supportive immuneboosters can be used in different combinations. Our study proposes a four-way attack to this fatal virus for the possible management of COVID-19 armed up with an antiviral, an antiparasitic drug, a cell-entry inhibitor, and a few supportive immune-boosters, which can be used in different combinations in different groups of people.

Comparing the Metabolome of a Caribbean Sponge to 420 FDA Approved Drugs, a Molecular Networking Approach

Planta Medica ◽  
2013 ◽  
Vol 79 (10) ◽  
Author(s):  
H Houson ◽  
J Schlesser ◽  
J Beverage ◽  
V Macherla ◽  
E Esquenazi
Keyword(s):  
Molecular Networking ◽  
Approved Drugs ◽  
Fda Approved Drugs
Sign in / Sign up

Export Citation Format

Share Document