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. Epub 2025 Mar 27.

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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Head and Neck Neoplasms* / drug therapy
  • Head and Neck Neoplasms* / enzymology
  • Head and Neck Neoplasms* / metabolism
  • Head and Neck Neoplasms* / pathology
  • Humans
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Kinase Inhibitors* / chemistry
  • Protein Kinase Inhibitors* / pharmacology
  • Proteolysis Targeting Chimera
  • Proteolysis* / drug effects
  • Squamous Cell Carcinoma of Head and Neck / drug therapy

Substances

  • Protein Kinase Inhibitors
  • Antineoplastic Agents
  • Proteasome Endopeptidase Complex
  • Proteolysis Targeting Chimera