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ACS Med Chem Lett. 2017 Sep 14;8(10):1042-1047. doi: 10.1021/acsmedchemlett.7b00247. eCollection 2017.

Targeting the Allosteric Site of Oncoprotein BCR-ABL as an Alternative Strategy for Effective Target Protein Degradation.

Author information

  • 1Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd., Kanagawa, Japan.
  • 2Divisions of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, Tokyo, Japan.

Abstract

Protein degradation technology based on hybrid small molecules is an emerging drug modality that has significant potential in drug discovery and as a unique method of post-translational protein knockdown in the field of chemical biology. Here, we report the first example of a novel and potent protein degradation inducer that binds to an allosteric site of the oncogenic BCR-ABL protein. BCR-ABL allosteric ligands were incorporated into the SNIPER (Specific and Nongenetic inhibitor of apoptosis protein [IAP]-dependent Protein Erasers) platform, and a series of in vitro biological assays of binding affinity, target protein modulation, signal transduction, and growth inhibition were carried out. One of the designed compounds, 6 (SNIPER(ABL)-062), showed desirable binding affinities against ABL1, cIAP1/2, and XIAP and consequently caused potent BCR-ABL degradation.

KEYWORDS:

BCR-ABL; E3 ubiquitin ligase; IAP; SNIPER; allosteric; protein degradation

PMID:
29057048
PMCID:
PMC5641955
[Available on 2018-10-12]
DOI:
10.1021/acsmedchemlett.7b00247
[PubMed]
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