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

  • J Biol Chem. 2025 May;301(5):108452. doi: 10.1016/j.jbc.2025.108452.
Meghri Katerji  1 ,  Knickole L Bergman  1 ,  Eric Lindberg  2 ,  Maxine R Rubin  1 ,  Marwa Afifi  3 ,  Amy L Funk  1 ,  Carolyn C Woodroofe  2 ,  Katherine Nyswaner  1 ,  Kamila Karpińska  4 ,  Remigiusz Serwa  5 ,  Steven D Cappell  3 ,  Anna Marusiak  4 ,  Rolf E Swenson  6 ,  John F Brognard  7
Affiliations
  • 1. Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute at Frederick, National Institutes of Health, Frederick, Maryland, USA.
  • 2. Chemistry and Synthesis Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Rockville, Maryland, USA.
  • 3. Laboratory of Cancer Genetics and Cell Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
  • 4. Laboratory of Molecular OncoSignalling, IMol Polish Academy of Sciences, Warsaw, Poland.
  • 5. Proteomic Core Facility, IMol Polish Academy of Sciences, Warsaw, Poland.
  • 6. Chemistry and Synthesis Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Rockville, Maryland, USA. Electronic address: [email protected].
  • 7. Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute at Frederick, National Institutes of Health, Frederick, Maryland, USA. Electronic address: [email protected].
PMID: 40157536 DOI: 10.1016/j.jbc.2025.108452
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.

Keywords
HNSCC; LZK; PROTAC; cancer therapy; noncatalytic functions; proteasome; protein degradation; protein kinase.