This technology describes the mechanism of action and use of compound FIN56, a specific inducer of ferroptosis.
Unmet Need: Tools for dissecting the mechanisms of ferroptosis
Ferroptosis is an iron-dependent form of regulated cell death that has been implicated in various diseases such as Alzheimer’s and many types of cancer. Modulation of ferroptosis is a promising and attractive strategy for developing therapeutics for these diseases. However, mechanistic studies have been difficult due to the lack of relevant research tools for studying ferroptosis, highlighting a need for further development.
The Technology: Ferroptosis-inducing compound FIN56 for research and drug development
This technology describes the mechanism of action and use of FIN56, a specific inducer of ferroptosis, using a combined experimental and computational framework. FIN56 induces cell death by downregulating glutathione peroxidase 4 (GPX4) protein, a lipid-repair enzyme, and by activating squalene synthase, which is important in cholesterol biosynthesis, resulting in depletion of coenzyme Q10 and subsequent iron-dependent accumulation of lipid hydroperoxides to lethal levels. Access to specific modulators of ferroptosis with defined mechanisms will expand research models for studying ferroptosis-mediated cell death, potentially enabling the discovery and development of additional ferroptosis modulators that may catapult therapeutic innovation for various diseases.
Applications:
- Research tool for ferroptosis mechanism dissection
- Research tool for therapeutic development and target validation
- Characterizing ferroptosis in various disease states (i.e. cancers, neurodegenerative diseases, traumatic injury, stroke, kidney degeneration, etc.)
Advantages:
- Specific ferroptosis inducer
- Defined mechanism enables research and validation of other modulators or potential therapeutic targets
- Provides a scalable, chemically synthesized and cost-effective library of compounds
- Multipurpose potential for a variety of research applications (i.e. transgenic mouse models, cell culture, etc.)
Lead Inventor:
Brent R. Stockwell, Ph.D.
Patent Information:
Patent Status
Related Publications:
Gaschler MM, Andia AA, Liu H, Csuka JM, Hurlocker B, Vaiana CA, Heindel DW, Zuckerman DS, Bos PH, Reznik E, Ye LF, Tyurina YY, Lin AJ, Shchepinov MS, Chan AY, Peguero-Pereira E, Fomich MA, Daniels JD, Bekish AV, Shmanai VV, Kagan VE, Mahal LK, Woerpel KA, Stockwell BR. “FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation” Nat Chem Biol. 2018 May; 14(5): 507–515.
Viswanathan VS, Ryan MJ, Dhruv HD, Gill S, Eichhoff OM, Seashore-Ludlow B, Kaffenberger SD, Eaton JK, Shimada K, Aguirre AJ, Viswanathan SR, Chattopadhyay S, Tamayo P, Yang WS, Rees MG, Chen S, Boskovic ZV, Javaid S, Huang C, Wu X, Tseng Y, Roider EM, Gao D, Cleary JM, Wolpin BM, Mesirov JP, Haber DA, Engelman JA, Boehm JS, Kotz JD, Hon CS, Chen Y, Hahn WC, Levesque MP, Doench JG, Berens ME, Shamji AF, Clemons PA, Stockwell BR, Schreiber SL. “Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway” Nature. 2017 Jul. 27; 547(7664): 453-457.
Shimada K, Skouta R, Kaplan A, Yang WS, Hayano M, Dixon SJ, Brown LM, Valenzuela CA, Wolpaw AJ, Stockwell BR. “Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis” Nat Chem Biol. 2016 Jul; 12(7): 497-503.
Yang WS, SriRamaratnam, Welsch ME, Shimada K, Skouta R, Viswanathan VS, Cheah JH, Clemons PA, Shamji AF, Clish CB, Brown LM, Girotti AW, Cornish VW, Schreiber SL, Stockwell BR. “Regulation of Ferroptotic Cancer Cell Death by GPX4” Cell. 2012 May; 149(5): 1060-1072.
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