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BioAssay: AID 624280

Broad Institute Inhibition of T.cruzi replication in culture Inhibitor Probe Project

The main goal is to identify new drugs for the treatment of Chagas disease. New drugs are needed because the only two drugs currently available are only effective against the early stages of disease and have significant toxicity to the patient. No drug is available to treat the chronic stage. This assay approach is intended to select drugs that will be effective against the early stages of more ..
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AID: 624280
Data Source: Broad Institute (2138_Inhibitor_Project)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
BioAssay Version:
Deposit Date: 2012-06-07
Modify Date: 2013-08-06

Data Table ( Complete ):           View Active Data    View All Data
BioActive Compound: Chemical Probe: 1    Active: 1
Related Experiments
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AIDNameTypeComment
624255Inhibition of T.cruzi proliferation in culture Measured in Cell-Based System Using Plate Reader - 2138-01_Inhibitor_SinglePoint_HTS_ActivityScreeningdepositor-specified cross reference: 77312 HTS compounds at SinglePoint in 2138-01 01 T. cruzi primary assay measuring Activity
651739Inhibition of T.cruzi proliferation in culture Measured in Cell-Based System Using Plate Reader - 2138-01_Inhibitor_SinglePoint_CherryPick_ActivityOtherdepositor-specified cross reference
651740Inhibition of T.cruzi proliferation in culture Measured in Cell-Based System Using Plate Reader - 2138-01_Inhibitor_SinglePoint_CherryPick_Activity_Set2Otherdepositor-specified cross reference
651742NIH/3T3 (mouse embryonic fibroblast) toxicity Measured in Cell-Based System Using Plate Reader - 2138-02_Inhibitor_SinglePoint_CherryPick_ActivityOtherdepositor-specified cross reference
651744NIH/3T3 (mouse embryonic fibroblast) toxicity Measured in Cell-Based System Using Plate Reader - 2138-02_Inhibitor_SinglePoint_CherryPick_Activity_Set2Otherdepositor-specified cross reference
651817NIH/3T3 (mouse embryonic fibroblast ) toxicity Measured in Cell-Based System Using Plate Reader - 2017-02_Inhibitor_Dose_CherryPick_Activity_Set2Confirmatorydepositor-specified cross reference
651818Intracellular Trypanosomes Measured in Cell-Based/Microorganism System Using Plate Reader - 2017-01_Inhibitor_Dose_CherryPick_Activity_Set3Confirmatorydepositor-specified cross reference
651844NIH/3T3 (mouse embryonic fibroblast) toxicity Measured in Cell-Based System Using Plate Reader - 2138-02_Inhibitor_Dose_DryPowder_ActivityConfirmatorydepositor-specified cross reference
651845Inhibition of T.cruzi proliferation in culture Measured in Cell-Based System Using Plate Reader - 2138-01_Inhibitor_Dose_DryPowder_ActivityConfirmatorydepositor-specified cross reference
651869Cidal vs. static assay: inhibition of T. cruzi (CAI/72) after prolonged treatment and treatment withdrawal Measured in Cell-Based System Using Imaging - 2138-08_Inhibitor_SinglePoint_DryPowder_Activity_Set2Otherdepositor-specified cross reference
651877Cidal vs. static assay: inhibition of T. cruzi (CAI/72) after prolonged treatment and treatment withdrawal Measured in Cell-Based System Using Imaging - 2138-08_Inhibitor_SinglePoint_DryPowder_ActivityOtherdepositor-specified cross reference
651881Inhibition of T. cruzi Tulahuen strain amastigotes in L-6 muscle cells Measured in Cell-Based and Microorganism Combination System Using Plate Reader - 2138-03_Inhibitor_Dose_CherryPick_ActivityConfirmatorydepositor-specified cross reference
651885Inhibition of intracellular CAI/72 strain of Trypanosoma cruzi in bovine embryo skeletal muscle cells: high content imaging Measured in Cell-Based System Using Imaging - 2138-07_Inhibitor_SinglePoint_DryPowder_ActivityConfirmatorydepositor-specified cross reference
651888Inhibition of Plasmodium falcipirum NF54 Measured in Cell-Based System Using Plate Reader - 2138-11_Inhibitor_Dose_CherryPick_ActivityConfirmatorydepositor-specified cross reference
651889Inhibition of Plasmodium falcipirum NF54 Measured in Cell-Based System Using Plate Reader - 2138-11_Inhibitor_Dose_DryPowder_ActivityConfirmatorydepositor-specified cross reference
651890Inhibition of T. cruzi Tulahuen strain amastigotes in L-6 muscle cells Measured in Cell-Based and Microorganism Combination System Using Plate Reader - 2138-03_Inhibitor_Dose_DryPowder_ActivityConfirmatorydepositor-specified cross reference
651891Inhibition of L. donovani axenic amastigotes Measured in Cell-Based System Using Plate Reader - 2138-04_Inhibitor_Dose_CherryPick_ActivityConfirmatorydepositor-specified cross reference
651892Inhibition of L. donovani axenic amastigotes Measured in Cell-Based System Using Plate Reader - 2138-04_Inhibitor_Dose_DryPowder_ActivityConfirmatorydepositor-specified cross reference
651893Inhibition of Trypanosoma brucei rhodesiense STIB900 Measured in Cell-Based System Using Plate Reader - 2138-05_Inhibitor_Dose_CherryPick_ActivityConfirmatorydepositor-specified cross reference
651894Inhibition of Trypanosoma brucei rhodesiense STIB900 Measured in Cell-Based System Using Plate Reader - 2138-05_Inhibitor_Dose_DryPowder_ActivityConfirmatorydepositor-specified cross reference
651895L-6 rat myocyte cell toxicity Measured in Cell-Based System Using Plate Reader - 2138-06_Inhibitor_Dose_DryPowder_ActivityConfirmatorydepositor-specified cross reference
651896L-6 rat myocyte cell toxicity Measured in Cell-Based System Using Plate Reader - 2138-06_Inhibitor_Dose_CherryPick_ActivityConfirmatorydepositor-specified cross reference
651897Inhibition of Trypanosoma cruzi Cruzain Measured in Biochemical System Using Plate Reader - 2138-09_Inhibitor_SinglePoint_DryPowder_ActivityConfirmatorydepositor-specified cross reference
651903Intracellular Trypanosomes Measured in Cell-Based/Microorganism System Using Plate Reader - 2017-01_Inhibitor_SinglePoint_HTS_Activity_Set2Screeningdepositor-specified cross reference
652275Inhibition of T.cruzi proliferation in culture Measured in Cell-Based System Using Plate Reader - 2138-01_Inhibitor_Dose_DryPowder_Activity_Set2Confirmatorydepositor-specified cross reference
652278Cidal vs. static assay: inhibition of T. cruzi (CAI/72) in J774 macrophages after prolonged compound treatment and treatment withdrawal Measured in Cell-Based System Using Imaging - 2138-13_Inhibitor_SinglePoint_DryPowder_Activity_Set2Otherdepositor-specified cross reference
652279Cidal vs. static assay: inhibition of T. cruzi (CAI/72) in J774 macrophages after prolonged compound treatment and treatment withdrawal Measured in Cell-Based System Using Imaging - 2138-13_Inhibitor_SinglePoint_DryPowder_ActivityOtherdepositor-specified cross reference
652280NIH/3T3 (mouse embryonic fibroblast) toxicity Measured in Cell-Based System Using Plate Reader - 2138-02_Inhibitor_Dose_DryPowder_Activity_Set2Confirmatorydepositor-specified cross reference
686919Inhibition of Trypanosoma cruzi Cruzain Measured in Biochemical System Using Plate Reader - 2138-09_Inhibitor_Dose_DryPowder_ActivityOtherdepositor-specified cross reference
Description:
Primary Collaborators:
Ana Rodriguez,NYU,New York, NY,Ana.Rodriguez@nyumc.org,212 263 6757 (Office)

Project Goal:

The main goal is to identify new drugs for the treatment of Chagas disease. New drugs are needed because the only two drugs currently available are only effective against the early stages of disease and have significant toxicity to the patient. No drug is available to treat the chronic stage. This assay approach is intended to select drugs that will be effective against the early stages of disease when parasites are found mainly extracellularly, but also drugs that will be effective against the chronic stage, where parasites are found inside host cells. Therefore we will select drugs that are either trypanostatic (expected to be effective in the acute phase of disease) or trypanocidal (expected to be effective against the chronic stage).

1)Probe attributes:
a.Inhibits intracellular parasitic replication (IC50 less than 500 nanomolar)
b.Non-toxic to host cells
c.100-fold selectivity towards inactivation of T. Cruzi vs. host cell toxicity
d.Preference given to Compounds that are trypanocidal
e.Chemically tractable compound

T. cruzi, Trypanosoma cruzi, Chagas
Biological Relevance:
Chagas disease is endemic to 18 Latin American countries, being the major cause of heart failure in the region. Chagas disease is caused by the parasite Trypanosoma cruzi, transmitted to humans in 3 ways: 1) Blood-feeding by various insect vectors that belong to the Reduviidae family, which live in cracks and crevices of poor-quality rural houses or in the wild. They emerge at night to bite and suck blood. The feces of the insects contain parasites, which can enter the wound left after the blood-meal, usually when it is scratched or rubbed; 2) Through transfusion with infected blood, 3) Congenitally, from infected mother to fetus.
The acute effects appear soon after infection and are generally seen in children. Symptoms can include fever, swelling at the site of the insect bite and of the lymph glands, and enlargement of the liver and spleen. The long-term effects can occur up to 20 years after infection. During the chronic phase of the disease, a proportion of patients develop clinical symptoms, which can include irreversible damage to internal organs such as the heart, esophagus and colon. Patients with these late-stage effects become progressively more ill and then die, usually from heart failure.
The number of infected people is estimated to be 13 million. Approximately 25 to 30% of chronically infected patients will suffer from irreversible damage to the heart and digestive tract. This will result in a high incidence of disability and death within the next 20 years, since no drugs are available for treatment of the chronic stage of the parasite. The estimated global burden of the disease is 649,000 disability adjusted life years (the number of healthy years of life lost due to premature death and disability) causing 14,000 deaths per year.
Categorized Comment - additional comments and annotations
From MLP Probe Report:
Probe count: 1
MLP Probe ML# for probe 1: ML341
PubChem Substance ID (SID) for probe 1: 152146810
PubChem Compound ID (CID) for probe 1: 44493436
Probe type for probe 1: Inhibitor
IC50/EC50 (nM) for probe 1: 0.9
Target for probe 1: Trypanosom a cruzi replication
Disease relevance for probe 1: Chagas Disease
Anti-target for probe 1: NIH3T3 host cell toxicity
Fold selectivity for probe 1: n/a
NCBI Book chapter link for probe 1: http://www.ncbi.nlm.nih.gov/books/NBK179828/ (ID: 3070070)
Grant number for probe 1: MH085673-01
PubMed Publication ID (PMID) for probe 1: 24287766
NCBI Book chapter title for probe 1: Identification of Diversity-Oriented Synthesis Derived Small Molecule, ML341, with Cidal Activity Against Trypanosoma cruzi
Result Definitions
TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
ScoreThe BioAssay activity ranking scoreInteger
1ML_NUMString
Additional Information
Grant Number: 1 R03 MH085673-01

Data Table (Concise)
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