Development of Novel LZK-Targeting PROTACs for Head and Neck Cancer
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.
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.
