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Selective Degradation of MLK3 by a Novel CEP1347-VHL-02 PROTAC Compound Limits the Oncogenic Potential of TNBC
Kamila Karpińska1, Dawid Mehlich1,2, Venkata R Sabbasani3
1Laboratory of Molecular OncoSignalling, IMol Polish Academy of Sciences, Warsaw 02-247, Poland.
Abstract:
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.
Insights
A new drug, CEP1347-VHL-02, effectively degrades Mixed-lineage protein kinase 3 (MLK3) in triple-negative breast cancer (TNBC) cells. This targeted approach shows promise for treating TNBC by reducing tumor cell growth and survival.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Triple-negative breast cancer (TNBC) presents a significant clinical challenge due to limited effective therapeutic options.
- Mixed-lineage protein kinase 3 (MLK3) is frequently overexpressed in TNBC and contributes to tumor progression.
- Targeting MLK3 is a potential strategy for novel TNBC therapies.
Purpose of the Study:
- To develop and characterize a novel selective degrader of MLK3 for potential TNBC treatment.
- To investigate the efficacy of the MLK3 degrader in preclinical TNBC models.
Main Methods:
- Utilized proteolysis-targeting chimera (PROTAC) technology to design CEP1347-VHL-02, linking a pan-MLK inhibitor (CEP1347) to a von Hippel-Lindau (VHL) E3 ligase ligand.
- Evaluated MLK3 degradation via the ubiquitin-proteasome system in various cancer cell lines.
- Assessed the compound's impact on TNBC cell proliferation, migration, cell cycle, and apoptosis in MDA-MB-468 cells.
Main Results:
- CEP1347-VHL-02 selectively induced MLK3 degradation through the ubiquitin-proteasome system without affecting other MLK family members.
- The compound demonstrated potent MLK3 degradation in TNBC cells.
- Treatment with CEP1347-VHL-02 significantly inhibited TNBC oncogenic activity, including reduced clonogenic potential, decreased migration, cell cycle arrest, and induced apoptosis.
Conclusions:
- CEP1347-VHL-02 is a novel and selective MLK3 degrader.
- This PROTAC-based compound represents a promising therapeutic strategy for targeting MLK3 in triple-negative breast cancer.
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