Leucine Zipper-bearing Kinase (LZK) has been identified as a novel therapeutic target in squamous cell carcinomas with 50% of head and neck squamous cell carcinoma (HNSCC) and lung squamous cell carcinomas (LSCC) patients showing amplifications or gains in LZK expression. Identifying successful therapies for the treatment of HNSCC or LSCC remains a significant unmet medical need.
Researchers at the National Institutes of Health (NIH) have discovered a technology involving synthesized LZK-targeting PROTACs which are comprised of a LZK kinase inhibitor, linker, and a E3-ligase-binding warhead targeting VHL. The LZK PROTACs suppress LZK expression, leading to complete degradation of the LZK kinase and suppression of both kinase-dependent and kinase-independent mechanisms of tumorigenesis. Specifically, the lead PROTAC suppresses LZK kinase-dependent stabilization of MYC. In addition, PROTAC-mediated LZK degradation leads to loss of expression of gain-of-function (GOF) mutant p53 in an LZK kinase-independent manner, where LZK acts as a likely scaffold to stabilize GOF mutant p53. The lead LZK PROTAC promotes almost complete cell death in cell line-based models of HNSCC and significant levels of cell death in LSCC models. Preclinical experiments in mice with tumors generated from HNSCC cell lines were used to further validate PROTACs as potential therapies for the treatment of LSCC and HNSCC.
The inventors welcome licensing and co-development interests to further develop and commercialize the technology.
- Therapeutic for treating head and neck squamous cell carcinoma (HNSCC) and lung squamous cell carcinomas (LSCC) via suppression of both GOF mutant p53 and c-MYC
- Potential therapeutic treatment for small-cell lung cancer and squamous ovarian cancer with amplified LZK
- The LZK inhibitor is effective at reducing c-MYC levels within an hour and maintains it for at least 72 hours
- The PROTACs also suppresses GOF p53
Funk A, et al. LZK inhibition suppresses HNSCC tumor growth via c-MYC and mutant p53. (To be submitted)
- U.S. Provisional: U.S. Provisional Patent Application Number 63/073,835 , Filed 02 Sep 2020