eEF2 Kinase As a Novel Oncology Target with Dual Effects in Protecting Normal Tissues and Enhancing Tumor Killing During Chemo- and Radiotherapy

 

eEF2 kinase is a key regulator of global protein synthesis that was discovered by Dr. Ryazanov (1). Inactivation of this kinase protects normal tissues from the damaging effects of chemotherapy and radiation (2). Significantly, inactivation of the kinase does not protect cancer cells and in fact enhances cancer cell killing by chemotherapeutic agents and nutrient deprivation (3, 4). The combination of protection of normal cells and increased tumor cell death during chemotherapeutic or radiation therapy represents an unprecedented approach to cancer therapy.

 

 

Preclinical evidence

 

Significant work has been carried out in the Ryazanov and other laboratories to demonstrate the utility of eEF2 kinase inhibition in killing tumor cells and protecting normal tissues (2-4). Specifically, knockout of eEF2 kinase protects cells and animals from toxic effects of radiation and chemotherapy (2; unpublished data). Furthermore, siRNA mediated eEF2 kinase knockdown has been shown both to sensitize tumor cell lines to chemotherapeutic agents and reduce tumor burden in a xenograft mouse model (3). Longevica developed a novel screening technology and generated a series of proprietary, highly selective small molecule eEF2 kinase inhibitors. These compounds have demonstrated in vitro the same activities as siRNA or gene knockouts, both in terms of protection of normal cells and sensitization of cancer cells. This dual activity embedded in a single molecule is unprecedented.

 

 

Opportunity

 

Because eEF2 kinase has been shown to be a common factor utilized by many types of tumors to cope with the stresses of hypoxia and chemotherapeutic treatment, it is anticipated that the Longevica proprietary eEF2 kinase inhibitors will demonstrate utility in a wide variety of malignancies. The combination of direct apoptotic effects and the ability to sensitize these cancers to conventional chemotherapeutic and radiation therapy, while preserving normal tissues, is extremely attractive. Additionally, the Longevica compounds should be combinable with a variety of chemotherapeutic agents.

 

 

Patent Position

 

Longevica has established proprietary screening, assay and small molecule composition of matter patents. Longevica has a portfolio of six issued US patents, including US patent 8,349,576 that covers the screening and assays necessary for running an eEF2 kinase program. The Longevica small molecule inhibitor composition of matter patent was filed in late 2013 and covers significant SAR related to highly selective and drug-like small molecules, and contains the molecular entities that are being profiled for development.

 

 

Licensing opportunity

 

Longevica is a research stage company that is seeking a collaboration partner to advance the development of eEF2 kinase inhibitors and is open to a variety of business arrangements.

 

 

About Longevica and the founder, Dr. Alexey Ryazanov

 

Longevica was formed to translate breakthrough research into programs that fill a significant unmet medical need and exhibit high commercial potential. The work at Longevica is inspired by the discoveries of the founder Dr. Alexey Ryazanov and is driven by pharmaceutical industry veterans. The combination of unprecedented science and drug discovery expertise results in programs of high novelty and advanced commercial potential. Dr. Ryazanov is a Professor of Pharmacology at Rutgers Robert Wood Johnson Medical School and a member of the Cancer Institute of New Jersey.

 

 

Contacts

 

Vladimir Ryazanov

vlad.a.ryazanov@gmail.com

 

 

References

 

1. A. G. Ryazanov, E. A. Shestakova, P. G. Natapov (1988) Phosphorylation of elongation factor 2 by EF-2 kinase affects rate of translation. Nature 334, 170-3.

 

2. H. P. Chu, Y. Liao, J. S. Novak, Z. Hu, J. J. Merkin, Y. Shymkiv, B. P. Braeckman, M. V. Dorovkov, A. Nguyen, P. M. Clifford, R. G. Nagele, D. E. Harrison, R. E. Ellis, A. G. Ryazanov (2014) Germline Quality Control: eEF2K Stands Guard to Eliminate Defective Oocytes. Developmental cell 28(5), 561-72.

 

3. I. Tekedereli, S. N. Alpay, C. D. Tavares, Z. E. Cobanoglu, T. S. Kaoud, I. Sahin, A. K. Sood, G. Lopez-Berestein, K. N. Dalby, B. Ozpolat (2012) Targeted silencing of elongation factor 2 kinase suppresses growth and sensitizes tumors to doxorubicin in an orthotopic model of breast cancer. PloS one 7, e41171.

 

4. G. Leprivier, M. Remke, B. Rotblat, A. Dubuc, A. R. Mateo, M. Kool, S. Agnihotri, A. El-Naggar, B. Yu, S. P. Somasekharan, B. Faubert, G. Bridon, C. E. Tognon, J. Mathers, R. Thomas, A. Li, A. Barokas, B. Kwok, M. Bowden, S. Smith, X. Wu, A. Korshunov, T. Hielscher, P. A. Northcott, J. D. Galpin, C. A. Ahern, Y. Wang, M. G. McCabe, V. P. Collins, R. G. Jones, M. Pollak, O. Delattre, M. E. Gleave, E. Jan, S. M. Pfister, C. G. Proud, W. B. Derry, M. D. Taylor, P. H. Sorensen (2013) The eEF2 kinase confers resistance to nutrient deprivation by blocking translation elongation. Cell 153, 1064-79.