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Identification of Small Molecules that Disrupt Signaling between ABL and Its Positive Regulator RIN1
Constitutively active BCR-ABL kinase fusions are causative mutations in the pathogenesis of hematopoietic neoplasias including chronic myelogenous leukemia (CML). Although these fusions have been successfully targeted with kinase inhibitors, drug-resistance and relapse continue to limit long-term su...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4374917/ https://www.ncbi.nlm.nih.gov/pubmed/25811598 http://dx.doi.org/10.1371/journal.pone.0121833 |
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author | Ting, Pamela Y. Damoiseaux, Robert Titz, Björn Bradley, Kenneth A. Graeber, Thomas G. Fernández-Vega, Virneliz Bannister, Thomas D. Chase, Peter Nair, Reji Scampavia, Louis Hodder, Peter Spicer, Timothy P. Colicelli, John |
author_facet | Ting, Pamela Y. Damoiseaux, Robert Titz, Björn Bradley, Kenneth A. Graeber, Thomas G. Fernández-Vega, Virneliz Bannister, Thomas D. Chase, Peter Nair, Reji Scampavia, Louis Hodder, Peter Spicer, Timothy P. Colicelli, John |
author_sort | Ting, Pamela Y. |
collection | PubMed |
description | Constitutively active BCR-ABL kinase fusions are causative mutations in the pathogenesis of hematopoietic neoplasias including chronic myelogenous leukemia (CML). Although these fusions have been successfully targeted with kinase inhibitors, drug-resistance and relapse continue to limit long-term survival, highlighting the need for continued innovative drug discovery. We developed a time-resolved Förster resonance energy transfer (TR-FRET) -based assay to identify compounds that disrupt stimulation of the ABL kinase by blocking its ability to bind the positive regulator RIN1. This assay was used in a high throughput screen (HTS) of two small molecule libraries totaling 444,743 compounds. 708 confirmed hits were counter-screened to eliminate off-target inhibitors and reanalyzed to prioritize compounds with IC(50) values below 10 μM. The CML cell line K562 was then used to identify five compounds that decrease MAPK1/3 phosphorylation, which we determined to be an indicator of RIN1-dependent ABL signaling. One of these compounds is a thiadiazole, and the other four are structurally related acyl piperidine amides. Notably, these five compounds lower cellular BCR-ABL1 kinase activity by blocking a positive regulatory interaction rather than directly inhibiting ABL catalytic function. |
format | Online Article Text |
id | pubmed-4374917 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-43749172015-04-04 Identification of Small Molecules that Disrupt Signaling between ABL and Its Positive Regulator RIN1 Ting, Pamela Y. Damoiseaux, Robert Titz, Björn Bradley, Kenneth A. Graeber, Thomas G. Fernández-Vega, Virneliz Bannister, Thomas D. Chase, Peter Nair, Reji Scampavia, Louis Hodder, Peter Spicer, Timothy P. Colicelli, John PLoS One Research Article Constitutively active BCR-ABL kinase fusions are causative mutations in the pathogenesis of hematopoietic neoplasias including chronic myelogenous leukemia (CML). Although these fusions have been successfully targeted with kinase inhibitors, drug-resistance and relapse continue to limit long-term survival, highlighting the need for continued innovative drug discovery. We developed a time-resolved Förster resonance energy transfer (TR-FRET) -based assay to identify compounds that disrupt stimulation of the ABL kinase by blocking its ability to bind the positive regulator RIN1. This assay was used in a high throughput screen (HTS) of two small molecule libraries totaling 444,743 compounds. 708 confirmed hits were counter-screened to eliminate off-target inhibitors and reanalyzed to prioritize compounds with IC(50) values below 10 μM. The CML cell line K562 was then used to identify five compounds that decrease MAPK1/3 phosphorylation, which we determined to be an indicator of RIN1-dependent ABL signaling. One of these compounds is a thiadiazole, and the other four are structurally related acyl piperidine amides. Notably, these five compounds lower cellular BCR-ABL1 kinase activity by blocking a positive regulatory interaction rather than directly inhibiting ABL catalytic function. Public Library of Science 2015-03-26 /pmc/articles/PMC4374917/ /pubmed/25811598 http://dx.doi.org/10.1371/journal.pone.0121833 Text en © 2015 Ting et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Ting, Pamela Y. Damoiseaux, Robert Titz, Björn Bradley, Kenneth A. Graeber, Thomas G. Fernández-Vega, Virneliz Bannister, Thomas D. Chase, Peter Nair, Reji Scampavia, Louis Hodder, Peter Spicer, Timothy P. Colicelli, John Identification of Small Molecules that Disrupt Signaling between ABL and Its Positive Regulator RIN1 |
title | Identification of Small Molecules that Disrupt Signaling between ABL and Its Positive Regulator RIN1 |
title_full | Identification of Small Molecules that Disrupt Signaling between ABL and Its Positive Regulator RIN1 |
title_fullStr | Identification of Small Molecules that Disrupt Signaling between ABL and Its Positive Regulator RIN1 |
title_full_unstemmed | Identification of Small Molecules that Disrupt Signaling between ABL and Its Positive Regulator RIN1 |
title_short | Identification of Small Molecules that Disrupt Signaling between ABL and Its Positive Regulator RIN1 |
title_sort | identification of small molecules that disrupt signaling between abl and its positive regulator rin1 |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4374917/ https://www.ncbi.nlm.nih.gov/pubmed/25811598 http://dx.doi.org/10.1371/journal.pone.0121833 |
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