ON012380: A Non-ATP Competitive Inhibitor of BCR-ABL for the Therapy of Imatinib-Resistant CMLs

Abstract

We have developed several novel small molecule inhibitors of BCR-ABL that inhibit the proliferation and induce apoptosis of CML cell lines that express the WT or the T315I mutant form of BCR-ABL. These compounds readily induced the downregulation of BCR-ABL auto-phosphorylation and STAT-5 phosphorylation. Using ON044580 as the lead compound, we have carried out chemical modification of the compound to facilitate the oral bio-availability of the compound. This resulted in the derivation of ON045590 which retained the BCR-ABL inhibitory activity as well as JAK2 inhibitory activity of the parent compound. Caco-2 cell bioavailability assays suggest that this compound is likely to be orally bio-available. We show that ON044850 destroys the Bcr-Abl/Jak2 protein Network, which is a large multi-component signaling structure maintained in an active state by members of the HSP90 chaperone complex. ON044850 blocks JAK2-mediated Tyr705 phosphorylation of STAT3 as well as Tyr177 of BCR-ABL. Our results also show that ON044580 inhibits NF-kB activation mediated by JAK2.

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Document Details

Document Type
Technical Report
Publication Date
May 01, 2009
Accession Number
ADA510718

Entities

People

  • E. Premkumar Reddy

Organizations

  • Temple University

Tags

DTIC Thesaurus Topics

  • Apoptosis
  • Body Weight
  • Cell Line
  • Cell Physiological Processes
  • Cells
  • Diseases And Disorders
  • Encapsulation
  • Fibroblasts
  • Hematologic Diseases
  • Inhibitors
  • Liquid Chromatography
  • Molecules
  • Myeloid Cells
  • Neoplasms
  • Phosphorylation
  • Therapy
  • Toxicity

Fields of Study

  • Biology

Readers

  • Breast cancer cell signaling and growth regulation.
  • Cellular and Molecular Pathways of Apoptosis.
  • Toxicology/Environmental Toxicology