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Leucine Zipper-bearing Kinase (LZK) -Targeting Degraders and Methods of Use

Summary
The National Cancer Institute (NCI) seeks research co-development partners and/or licensees for Leucine Zipper-bearing Kinase (LZK) -targeting proteolysis-targeting chimeras (PROTACs) as a therapeutic for treating head and neck, lung and ovarian squamous cell carcinoma, as well as small cell lung cancers which over-express LZK.
NIH Reference Number
E-163-2020
Product Type
Keywords
  • Leucine Zipper-bearing Kinase, LZK, MAP3K13, Proteolysis-targeting Chimera, PROTAC, LZK-targeting PROTACs, Degraders, Head and Neck Squamous Cell Carcinoma, HNSCC, Amplified oncogenes, Ovarian cancer, Small Cell Lung Cancer, LSCC, VHL Warhead, Brognard
Collaboration Opportunity
This invention is available for licensing and co-development.
Contact
Description of Technology

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.   

Potential Commercial Applications
  • 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
Competitive Advantages
  • 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
Inventor(s)

John Brognard Ph.D. (NCI), Rolf Swenson Ph.D. (NHLBI), Amy Funk Ph.D. (NCI), Carolyn Woodroofe Ph.D. (NHLBI), Katherine Nyswaner MSc (NCI)

Development Stage
Publications

Funk A, et al. LZK inhibition suppresses HNSCC tumor growth via c-MYC and mutant p53. (To be submitted) 

Patent Status
  • U.S. Provisional: U.S. Provisional Patent Application Number 63/073,835 , Filed 02 Sep 2020
Therapeutic Area
Updated
Monday, November 30, 2020