Selective Degradation of MLK3 by a Novel CEP1347-VHL-02 PROTAC Compound Limits the Oncogenic Potential of TNBC
Triple-negative breast cancer (TNBC) is associated with poor prognosis because of the lack of effective therapies. Mixed-lineage protein kinase 3 (MLK3) is a protein that is often upregulated in TNBC and involved in driving the tumorigenic potential of cancer cells. Here, we present a selective MLK3 degrader, CEP1347-VHL-02, based on the pan-MLK inhibitor CEP1347 and a ligand for E3 ligase von Hippel-Lindau (VHL) by employing proteolysis-targeting chimera (PROTAC) technology. Our compound effectively targeted MLK3 for degradation via the ubiquitin-proteasome system in several cell line models but did not degrade other MLK family members. Furthermore, we showed that CEP1347-VHL-02 robustly degraded MLK3 and inhibited its oncogenic activity in TNBC, measured as a reduction of clonogenic and migratory potential, cell cycle arrest, and the induction of apoptosis in MDA-MB-468 cells. In conclusion, we present CEP1347-VHL-02 as a novel MLK3 degrader that may be a promising new strategy to target MLK3 in TNBC.
Authors
- Anna A. Marusiak (ORCID: https://orcid.org/0000-0001-8907-3131)
- Vi Nguyen-Phuong Truong (ORCID: https://orcid.org/0000-0002-6099-767X)
- Venkata R. Sabbasani (ORCID: https://orcid.org/0000-0002-4558-2812)
- Kamila Karpińska (ORCID: https://orcid.org/0000-0002-7349-5038)
- John Brognard (ORCID: https://orcid.org/0000-0002-9243-6615)
- Remigiusz Adam Serwa (ORCID: https://orcid.org/0000-0002-4684-3754)
- Rolf E. Swenson (ORCID: https://orcid.org/0000-0001-7804-7202)
- Michał Łomiak (ORCID: https://orcid.org/0000-0001-9109-8776)
- Dawid Mehlich (ORCID: https://orcid.org/0000-0003-0455-6965)
- Pedro Torres‐Ayuso (ORCID: https://orcid.org/0000-0003-2213-9014)
- Katarzyna Wróbel
Institutions
- National Institutes of Health (US)
- National Heart, Lung, and Blood Institute (US)
- National Cancer Institute (US)
- Temple University (US)
- Polish Academy of Sciences (PL)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-08-29
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c00577
- Citations
- 7
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 1.64
Funders
- Temple University
- Polsko-Amerykanska Komisja Fulbrighta
- Narodowe Centrum Nauki
- Narodowa Agencja Wymiany Akademickiej
- National Institutes of Health
- Fox Chase Cancer Center
- National Cancer Institute