TY - JOUR
T1 - Selective Degradation of MLK3 by a Novel CEP1347-VHL-02 PROTAC Compound Limits the Oncogenic Potential of TNBC
AU - Karpińska, Kamila
AU - Mehlich, Dawid
AU - Sabbasani, Venkata R
AU - Łomiak, Michał
AU - Torres-Ayuso, Pedro
AU - Wróbel, Katarzyna
AU - Truong, Vi Nguyen-Phuong
AU - Serwa, Remigiusz
AU - Swenson, Rolf E
AU - Brognard, John
AU - Marusiak, Anna A
N1 - Publisher Copyright:
© 2024 The Authors. Published by American Chemical Society.
PY - 2024/9/12
Y1 - 2024/9/12
N2 - 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.
AB - 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.
KW - Antineoplastic Agents/pharmacology
KW - Apoptosis/drug effects
KW - Cell Line, Tumor
KW - Cell Proliferation/drug effects
KW - Female
KW - Humans
KW - Mitogen-Activated Protein Kinase Kinase Kinase 11
KW - Protein Kinase Inhibitors/pharmacology
KW - Proteolysis/drug effects
KW - Triple Negative Breast Neoplasms/drug therapy
KW - Von Hippel-Lindau Tumor Suppressor Protein/metabolism
UR - http://www.scopus.com/inward/record.url?scp=85202724008&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.4c00577
DO - 10.1021/acs.jmedchem.4c00577
M3 - Article
C2 - 39207123
SN - 0022-2623
VL - 67
SP - 15012
EP - 15028
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 17
ER -
