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Open Access Publications from the University of California

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

  • Author(s): Ting, PY
  • Damoiseaux, R
  • Titz, B
  • Bradley, KA
  • Graeber, TG
  • Fernández-Vega, V
  • Bannister, TD
  • Chase, P
  • Nair, R
  • Scampavia, L
  • Hodder, P
  • Spicer, TP
  • Colicelli, J
  • et al.

© 2015 Ting et al. 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 IC50values 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.

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