期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 62, 期 11, 页码 5522-5540出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.9b00455
关键词
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资金
- Multiple Myeloma Research Foundation
- NSERC
- CIHR
- Arnie Charbonneau Cancer Research Institute
- Alberta Children's Hospital Foundation
- Canada Research Chairs program
- Alberta Innovates Technology Futures
- Alberta Children's Hospital Research Institute
Protein-protein interactions (PPIs) have emerged as significant targets for therapeutic development, owing to their critical nature in diverse biological processes. An ideal PPI-based target is the protein myeloid cell leukemia 1 (MCL1), a critical prosurvival factor in cancers such as multiple myeloma where MCL1 levels directly correlate to disease progression. Current strategies for halting the antiapoptotic properties of MCL1 revolve around inhibiting its sequestration of proapoptotic factors. Existing inhibitors disrupt endogenous regulatory proteins; however, this strategy actually leads to an increase of MCL1 protein levels. Here, we show the development of hetero-bifunctional small molecules capable of selectively targeting MCL1 using a proteolysis targeting chimera (PROTAC) methodology leading to successful degradation. We have confirmed the involvement of the E3 ligase CUL4A-DDB1 cereblon ubiquitination pathway, making these PROTACs a first step toward a new class of antiapoptotic B-cell lymphoma 2 family protein degraders.
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