2. Academic Validation
  3. Selective Degradation of MLK3 by a Novel CEP1347-VHL-02 PROTAC Compound Limits the Oncogenic Potential of TNBC

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

  • J Med Chem. 2024 Sep 12;67(17):15012-15028. doi: 10.1021/acs.jmedchem.4c00577.
Kamila Karpińska 1,  Dawid Mehlich 1 2,  Venkata R Sabbasani 3,  Michał Łomiak 1,  Pedro Torres-Ayuso 4,  Katarzyna Wróbel 1,  Vi Nguyen-Phuong Truong 1,  Remigiusz Serwa 5,  Rolf E Swenson 3,  John Brognard 2,  Anna A Marusiak 1
Affiliations

Affiliations

  • 1 Laboratory of Molecular OncoSignalling, IMol Polish Academy of Sciences, Warsaw 02-247, Poland.
  • 2 Laboratory of Cell and Developmental Signaling, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, United States.
  • 3 Chemistry and Synthesis Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, United States.
  • 4 Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania 19140, United States.
  • 5 Proteomic Core Facility, IMol Polish Academy of Sciences, Warsaw 02-247, Poland.
PMID: 39207123 DOI: 10.1021/acs.jmedchem.4c00577
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.

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