Evidence map›Paper›PMID 26655304›Full record

ArticleMolecular pharmacology2016

Biological Characterization of an Improved Pyrrole-Based Colchicine Site Agent Identified through Structure-Based Design.

Cristina C Rohena, Nakul S Telang, Chenxiao Da, April L Risinger, James A Sikorski, Glen E Kellogg, John T Gupton, Susan L Mooberry

Erratum issuedOpen access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular pharmacology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 6 papers.

0numbers the graph read from it
0cells of the map it votes in
6citing papers in PubMed
0.9field-weighted citation impact, top 25% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

6 citing papers in PubMed, 10 citations in OpenAlex.

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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

8 authors at 3 institutions in 1 country.

Cristina C RohenaDepartment of Pharmacology and Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas (C.C.R., A.L.R., S.L.M.); Department of Chemistry University of Richmond, Richmond Virginia (N.T., J.T.G.); Department of Medicinal Chemistry and Institute of Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, Virginia (C.D., G.E.K.); and Medicinal Chemistry & Drug Discovery, Chesterfield, Missouri (J.A.S.).
Nakul S TelangDepartment of Pharmacology and Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas (C.C.R., A.L.R., S.L.M.); Department of Chemistry University of Richmond, Richmond Virginia (N.T., J.T.G.); Department of Medicinal Chemistry and Institute of Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, Virginia (C.D., G.E.K.); and Medicinal Chemistry & Drug Discovery, Chesterfield, Missouri (J.A.S.).
Chenxiao DaDepartment of Pharmacology and Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas (C.C.R., A.L.R., S.L.M.); Department of Chemistry University of Richmond, Richmond Virginia (N.T., J.T.G.); Department of Medicinal Chemistry and Institute of Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, Virginia (C.D., G.E.K.); and Medicinal Chemistry & Drug Discovery, Chesterfield, Missouri (J.A.S.).
April L RisingerDepartment of Pharmacology and Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas (C.C.R., A.L.R., S.L.M.); Department of Chemistry University of Richmond, Richmond Virginia (N.T., J.T.G.); Department of Medicinal Chemistry and Institute of Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, Virginia (C.D., G.E.K.); and Medicinal Chemistry & Drug Discovery, Chesterfield, Missouri (J.A.S.).
James A SikorskiDepartment of Pharmacology and Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas (C.C.R., A.L.R., S.L.M.); Department of Chemistry University of Richmond, Richmond Virginia (N.T., J.T.G.); Department of Medicinal Chemistry and Institute of Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, Virginia (C.D., G.E.K.); and Medicinal Chemistry & Drug Discovery, Chesterfield, Missouri (J.A.S.).
Glen E KelloggDepartment of Pharmacology and Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas (C.C.R., A.L.R., S.L.M.); Department of Chemistry University of Richmond, Richmond Virginia (N.T., J.T.G.); Department of Medicinal Chemistry and Institute of Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, Virginia (C.D., G.E.K.); and Medicinal Chemistry & Drug Discovery, Chesterfield, Missouri (J.A.S.).
John T GuptonDepartment of Pharmacology and Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas (C.C.R., A.L.R., S.L.M.); Department of Chemistry University of Richmond, Richmond Virginia (N.T., J.T.G.); Department of Medicinal Chemistry and Institute of Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, Virginia (C.D., G.E.K.); and Medicinal Chemistry & Drug Discovery, Chesterfield, Missouri (J.A.S.).
Susan L MooberryDepartment of Pharmacology and Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas (C.C.R., A.L.R., S.L.M.); Department of Chemistry University of Richmond, Richmond Virginia (N.T., J.T.G.); Department of Medicinal Chemistry and Institute of Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, Virginia (C.D., G.E.K.); and Medicinal Chemistry & Drug Discovery, Chesterfield, Missouri (J.A.S.). Mooberry@uthscsa.edu.
The University of Texas Health Science Center at San Antonio · USVirginia Commonwealth University · USUniversity of Richmond · US

Funding

The Synthesis and Biological Evaluation of Pyrrole Containing Marine Natural ProdR15CA067236 · NCI · UNIVERSITY OF RICHMOND · PI GUPTON, JOHN T. · 1996 to 2012
$882k
NCI NIH HHS R15 CA067236NCI NIH HHS R15-CA67236-05A1
6 · The paper itself

Abstract

A refined model of the colchicine site on tubulin was used to design an improved analog of the pyrrole parent compound, JG-03-14. The optimized compound, NT-7-16, was evaluated in biological assays that confirm that it has potent activities as a new colchicine site microtubule depolymerizer. NT-7-16 exhibits antiproliferative and cytotoxic activities against multiple cancer cell lines, with IC(50) values of 10-16 nM, and it is able to overcome drug resistance mediated by the expression of P-glycoprotein and the βIII isotype of tubulin. NT-7-16 initiated the concentration-dependent loss of cellular microtubules and caused the formation of abnormal mitotic spindles, leading to mitotic accumulation. The direct interaction of NT-7-16 with purified tubulin was confirmed, and it was more potent than combretastatin A-4 in these assays. Binding studies verified that NT-7-16 binds to tubulin within the colchicine site. The antitumor effects of NT-7-16 were evaluated in an MDA-MB-435 xenograft model and it had excellent activity at concentrations that were not toxic. A second compound, NT-9-21, which contains dichloro moieties in place of the 3,5-dibromo substituents of NT-7-16, had a poorer fit within the colchicine site as predicted by modeling and the Hydropathic INTeractions score. Biological evaluations showed that NT-9-21 has 10-fold lower potency than NT-7-16, confirming the modeling predictions. These studies highlight the value of the refined colchicine-site model and identify a new pyrrole-based colchicine-site agent with potent in vitro activities and promising in vivo antitumor actions.

Indexed as

AnimalsBinding SitesColchicineCrystallography, X-RayFemaleHeLa CellsHumansMiceMice, NudeMolecular Docking SimulationPyrrolesStructure-Activity RelationshipTubulinColchicinePyrrolesTubulin

Identifiers

PMID26655304
PMCPMC4727124
OpenAlexW2341351487

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.