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- Title
Identification of Small Molecules that Disrupt Signaling between ABL and Its Positive Regulator RIN1.
- Authors
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
- 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.
- Subjects
CELLULAR signal transduction; GENETIC regulation; GENETIC mutation; DRUG resistance; DRUG delivery systems
- Publication
PLoS ONE, 2015, Vol 10, Issue 3, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0121833