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

Triple-negative breast\ncancer (TNBC) is associated with poor prognosis\nbecause of the lack of effective therapies. Mixed-lineage protein\nkinase 3 (MLK3) is a protein that is often upregulated in TNBC and\ninvolved in driving the tumorigenic potential of cancer cells. Here,\nwe present a selective MLK3 degrader, CEP1347-VHL-02, based on the\npan-MLK inhibitor CEP1347 and a ligand for E3 ligase von Hippel–Lindau\n(VHL) by employing proteolysis-targeting chimera (PROTAC) technology.\nOur compound effectively targeted MLK3 for degradation via the ubiquitin-proteasome\nsystem in several cell line models but did not degrade other MLK family\nmembers. Furthermore, we showed that CEP1347-VHL-02 robustly degraded\nMLK3 and inhibited its oncogenic activity in TNBC, measured as a reduction\nof clonogenic and migratory potential, cell cycle arrest, and the\ninduction of apoptosis in MDA-MB-468 cells. In conclusion, we present\nCEP1347-VHL-02 as a novel MLK3 degrader that may be a promising new\nstrategy to target MLK3 in TNBC.