Development of a Potent Protein Degrader against Oncogenic BCR-ABL Protein

Chem Pharm Bull (Tokyo). 2019;67(3):165-172. doi: 10.1248/cpb.c18-00703.


Chromosomal translocation occurs in some cancer cells, resulting in the expression of aberrant oncogenic fusion proteins that include BCR-ABL in chronic myelogenous leukemia (CML). Inhibitors of ABL tyrosine kinase, such as imatinib and dasatinib, exhibit remarkable therapeutic effects, although emergence of drug resistance hampers the therapy during long-term treatment. An alternative approach to treat CML is to downregulate expression of the BCR-ABL protein. Recently, we have devised a protein knockdown system by hybrid molecules named Specific and Nongenetic inhibitor of apoptosis protein [IAP]-dependent Protein Erasers (SNIPER). This system is designed to induce IAP-mediated ubiquitylation and proteasomal degradation of target proteins. In this review, we describe the development of SNIPER against BCR-ABL, and discuss the features and prospect for treatment of CML.

Keywords: BCR-ABL; E3 ubiquitin ligase; chronic myelogenous leukemia (CML); degrader; proteasome; protein knockdown.

Publication types

  • Review

MeSH terms

  • Antineoplastic Agents / therapeutic use
  • Down-Regulation
  • Drug Resistance, Neoplasm
  • Fusion Proteins, bcr-abl / antagonists & inhibitors*
  • Fusion Proteins, bcr-abl / metabolism
  • Humans
  • Inhibitor of Apoptosis Proteins / metabolism
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism*
  • Oncogenes*
  • Proteasome Endopeptidase Complex / metabolism
  • Ubiquitination


  • Antineoplastic Agents
  • Inhibitor of Apoptosis Proteins
  • Fusion Proteins, bcr-abl
  • Proteasome Endopeptidase Complex