Discovery of potent and selective PROTACs for the protein kinase LZK for the treatment of head and neck cancer

Leucine zipper-bearing kinase (LZK) is overexpressed in 20% of head and neck squamous cell carcinoma (HNSCC) cases and has emerged as a promising therapeutic target in this cancer subtype. LZK promotes HNSCC survival and proliferation by stabilizing c-MYC and GOF-p53 in kinase-dependent and -independent manners, respectively. Herein, we developed a new series of LZK degraders utilizing proteolysis-targeting chimera (PROTAC) technology by modulating the linker region or LZK warhead of LZK-targeting PROTAC-21A, previously developed by our laboratory. Among the 27 PROTACs synthesized and tested, PROTAC 17 was found to be the most potent, degrading LZK at 250 nM and suppressing HNSCC viability at 500 nM. In summary, our lead PROTAC effectively targeted LZK for proteasomal degradation and inhibited oncogenic activity in HNSCC cell lines with amplified LZK.

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Publication Details

Journal
Journal of Biological Chemistry
Published
2025-03-29
DOI
https://doi.org/10.1016/j.jbc.2025.108452
Citations
2
Primary Topic
Protein Degradation and Inhibitors
Type
article
Field-Weighted Citation Impact
1.61
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article

Discovery of potent and selective PROTACs for the protein kinase LZK for the treatment of head and neck cancer

Carolyn C. Woodroofe, Anna A. Marusiak, Kamila Karpińska, Eric Lindberg et al.
2 citations
Journal of Biological Chemistry
Protein Degradation and Inhibitors
1.61
article

Discovery of potent and selective PROTACs for the protein kinase LZK for the treatment of head and neck cancer

Carolyn C. Woodroofe, Anna A. Marusiak, Kamila Karpińska, Eric Lindberg, K. Bergman, John Brognard, Remigiusz Adam Serwa, Rolf E. Swenson, Amy L. Funk, Katherine M. Nyswaner, Maxine R. Rubin, Meghri Katerji
article en
2 citations

Abstract

Leucine zipper-bearing kinase (LZK) is overexpressed in 20% of head and neck squamous cell carcinoma (HNSCC) cases and has emerged as a promising therapeutic target in this cancer subtype. LZK promotes HNSCC survival and proliferation by stabilizing c-MYC and GOF-p53 in kinase-dependent and -independent manners, respectively. Herein, we developed a new series of LZK degraders utilizing proteolysis-targeting chimera (PROTAC) technology by modulating the linker region or LZK warhead of LZK-targeting PROTAC-21A, previously developed by our laboratory. Among the 27 PROTACs synthesized and tested, PROTAC 17 was found to be the most potent, degrading LZK at 250 nM and suppressing HNSCC viability at 500 nM. In summary, our lead PROTAC effectively targeted LZK for proteasomal degradation and inhibited oncogenic activity in HNSCC cell lines with amplified LZK.

Journal of Biological ChemistryVol. 301(5)
National Institutes of Health (US), National Heart, Lung, and Blood Institute (US), Frederick National Laboratory for Cancer Research (US), National Cancer Institute (US), Polish Academy of Sciences (PL)
Good health and well-being
Openalex Percentile: Top 18%
Protein Degradation and Inhibitors
1.61
DOIOpen Access PDFOpenAlex
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