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Review
. 2019;67(3):165-172.
doi: 10.1248/cpb.c18-00703.

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

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Review

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

Norihito Shibata et al. Chem Pharm Bull (Tokyo). .
Free article

Abstract

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.

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