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

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  • Shibata Norihito
    Divisions of Molecular Target and Gene Therapy Products, National Institute of Health Sciences
  • Ohoka Nobumichi
    Divisions of Molecular Target and Gene Therapy Products, National Institute of Health Sciences
  • Hattori Takayuki
    Divisions of Molecular Target and Gene Therapy Products, National Institute of Health Sciences
  • Naito Mikihiko
    Divisions of Molecular Target and Gene Therapy Products, National Institute of Health Sciences

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Abstract

<p>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.</p>

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