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.