From Inhibition to Degradation: Targeting the Antiapoptotic Protein Myeloid Cell Leukemia 1 (MCL1)
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Abstract
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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dMCL1-2 degrades Mcl-1 in OPM2 and MM.1S multiple myeloma cell lines.
“There are reported Mcl-1 PROTACs [45, 58], dMCL1-2 as a representative, which degrades Mcl-1 in OPM2 and MM.1S MM cell lines.”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [45]
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Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies
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“The discovery of PROTAC MCL-1 and BCL-2 degraders (Figure 1) have been reported recently [38,39].”
BackgroundWang, Z., He, N., Guo, Z., Niu, C., Song, T., Guo, Y., Cao, K., Wang, A., Zhu, J., Zhang, X., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b00919 · Cited by 120 · see citing works
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- Authors
- Papatzimas, J. W., Gorobets, E., Maity, R., Muniyat, M. I., MacCallum, J. L., Neri, P., Bahlis, N. J., & Derksen, D. J.
- Affiliations
- University of Calgary (CA)
- Corresponding author
- Bahlis, Nizar J.
- Derksen, Darren J.
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2019-05-22
- Volume
- 62
- Issue
- 11
- Pages
- 5522-5540
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2945824284
- Cited by
- 103
- References
- 62
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 10 · 2023: 10 · 2022: 17 · 2021: 19 · 2020: 22 · 2019: 8
- FWCI
- 5.71
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- ChemRxiv (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Figshare (submittedVersion, cc-by-nc-nd)
- Funders
- Government of Canada
- Multiple Myeloma Research Foundation
- Alberta Children's Hospital Foundation
- Alberta Innovates - Technology Futures
- Canada Research Chairs Program
- Arnie Charbonneau Cancer Institute, University of Calgary
- Alberta Children's Hospital Research Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- Mcl-1, PROTACs, protein degradation, Bcl-2 family proteins, apoptosis, multiple myeloma, E3 ubiquitin ligase, anti-apoptotic proteins
- MeSH terms
- Cell Line, Humans, Indoles, Models, Molecular, Protein Conformation, Sulfonamides, Proteasome Endopeptidase Complex, Ubiquitination, Proteolysis, Myeloid Cell Leukemia Sequence 1 Protein
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