Selective Degradation of MLK3 by a Novel CEP1347-VHL-02 PROTAC Compound Limits the Oncogenic Potential of TNBC

• Published in: Journal of medicinal chemistry Vol. 67; no. 17; pp. 15012 - 15028
• Main Authors: Karpińska, Kamila, Mehlich, Dawid, Sabbasani, Venkata R., Łomiak, Michał, Torres-Ayuso, Pedro, Wróbel, Katarzyna, Truong, Vi Nguyen-Phuong, Serwa, Remigiusz, Swenson, Rolf E., Brognard, John, Marusiak, Anna A.
• Format: Journal Article
• Language: English
• Published: WASHINGTON Amer Chemical Soc 12.09.2024; American Chemical Society
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry, Medicinal; Female; Humans; Life Sciences & Biomedicine; Mitogen-Activated Protein Kinase Kinase Kinase 11; Pharmacology & Pharmacy; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Proteolysis - drug effects; Science & Technology; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; Von Hippel-Lindau Tumor Suppressor Protein - metabolism; ACTIVATION; INVASION; COMPUTATIONAL PLATFORM; PHOSPHORYLATION; MIXED-LINEAGE KINASE-3; B-RAF; INHIBITOR; CANCER CELL-MIGRATION
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.4c00577

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.