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Identification of small molecules that disrupt signaling between ABL and its positive regulator RIN1

Academic Article
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Overview

authors

  • Ting, P. Y.
  • Damoiseaux, R.
  • Titz, B.
  • Bradley, K. A.
  • Graeber, T. G.
  • Fernandez-Vega, V.
  • Bannister, Thomas
  • Chase, P.
  • Nair, R.
  • Scampavia, Louis
  • Hodder, Peter
  • Spicer, Timothy
  • Colicelli, J.

publication date

  • March 2015

journal

  • PLoS One  Journal

abstract

  • 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 IC50 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.

subject areas

  • Biflavonoids
  • Catechin
  • Fluorescence Resonance Energy Transfer
  • Fusion Proteins, bcr-abl
  • High-Throughput Screening Assays
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • K562 Cells
  • Mitogen-Activated Protein Kinase 1
  • Phosphorylation
  • Protein Binding
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-abl
  • Reproducibility of Results
  • Signal Transduction
  • Small Molecule Libraries
  • Time Factors
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Identity

PubMed Central ID

  • PMC4374917

International Standard Serial Number (ISSN)

  • 1932-6203

Digital Object Identifier (DOI)

  • 10.1371/journal.pone.0121833

PubMed ID

  • 25811598
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Additional Document Info

start page

  • e0121833

volume

  • 10

issue

  • 3

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