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Angew Chem Int Ed Engl. 2016 Jan 11;55(2):807-10. doi: 10.1002/anie.201507634. Epub 2015 Nov 23.

Modular PROTAC Design for the Degradation of Oncogenic BCR-ABL.

Author information

1
Departments of Chemistry; Molecular, Cellular & Developmental Biology; Pharmacology, Yale University, New Haven, CT 06511 (USA).
2
Departments of Chemistry; Molecular, Cellular & Developmental Biology; Pharmacology, Yale University, New Haven, CT 06511 (USA). craig.crews@yale.edu.

Abstract

Proteolysis Targeting Chimera (PROTAC) technology is a rapidly emerging alternative therapeutic strategy with the potential to address many of the challenges currently faced in modern drug development programs. PROTAC technology employs small molecules that recruit target proteins for ubiquitination and removal by the proteasome. The synthesis of PROTAC compounds that mediate the degradation of c-ABL and BCR-ABL by recruiting either Cereblon or Von Hippel Lindau E3 ligases is reported. During the course of their development, we discovered that the capacity of a PROTAC to induce degradation involves more than just target binding: the identity of the inhibitor warhead and the recruited E3 ligase largely determine the degradation profiles of the compounds; thus, as a starting point for PROTAC development, both the target ligand and the recruited E3 ligase should be varied to rapidly generate a PROTAC with the desired degradation profile.

KEYWORDS:

E3 ubiquitin ligases; cancer; drug design; inhibitors; protein degradation

PMID:
26593377
PMCID:
PMC4733637
DOI:
10.1002/anie.201507634
[Indexed for MEDLINE]
Free PMC Article

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