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
  • 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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