Modular PROTAC Design for the Degradation of Oncogenic BCR-ABL

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...

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Bibliographic Details
Published in:Angewandte Chemie (International ed.) 2016-01, Vol.55 (2), p.807-810
Main Authors: Lai, Ashton C., Toure, Momar, Hellerschmied, Doris, Salami, Jemilat, Jaime-Figueroa, Saul, Ko, Eunhwa, Hines, John, Crews, Craig M.
Format: Article
Language:English
Subjects:
Abl protein
BCR protein
Binding
cancer
Cell Line
Cell Line, Tumor
Degradation
drug design
Drug development
E3 ubiquitin ligases
Fusion protein
Fusion Proteins, bcr-abl - metabolism
Humans
Inhibitors
Modular design
Proteasomes
protein degradation
Proteins
Proteolysis
Strategy
Technology
Ubiquitin-protein ligase
Ubiquitination
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Summary: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. Induced protein degradation is an emerging field that has the potential to overcome many challenges faced by traditional inhibitor‐based drug design. A modular approach to PROTAC design is presented that enables targeted degradation of the therapeutically relevant BCR‐ABL oncogenic protein.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.201507634