Selective Degradation of MLK3 by a Novel PROTAC Limits the Oncogenic Potential of TNBC
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.
About the Cancer Cell Signaling & Therapeutics Lab
The Cancer Cell Signaling and Therapeutic Lab’s mission is to uncover the molecular drivers of cancers with limited treatment options and translate these discoveries into targeted therapies. By identifying new vulnerabilities in tumor biology, we aim to develop more precise treatments that improve survival while minimizing toxicity. Ultimately, our goal is to deliver therapies that extend and improve the lives of patients facing the greatest unmet needs.
