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Iodonium Analogs as Inhibitors of NADPH Oxidases and other Flavin Dehydrogenases and their Use for Treating Cancer

Summary
The National Cancer Institute (NCI) seeks research co-development partners and/or licensees for further development of novel iodonium analogs. These iodonium analogs inhibit NADPH oxidases (NOX) and other flavin dehydrogenases to slow tumor growth.
NIH Reference Number
E-116-2014
Product Type
Keywords
  • Pre-cancerous Lesions, NADPH oxidases, NOX, Flavin Dehydrogenases, Diphenylene Iodonium, DPI, Di-thienyl-iodonium, DTI, Reactive Oxygen Species, ROS, Doroshow
Collaboration Opportunity
This invention is available for licensing and co-development.
Contact
Description of Technology

Diverse human cancers like colorectal, pancreatic, ovarian, melanoma, and pre-cancers express NADPH oxidases (NOX) at high levels. Reactive oxygen species (ROS) produced from metabolic reactions catalyzed by NOX in tumors are essential to the tumor’s growth. Though drugs that inhibit ROS production by NOX could be effective against a variety of human cancers, these types of drugs are not widely available.

Investigators at the Developmental Therapeutics Branch of the National Cancer Institute (NCI) have synthesized novel analogs of diphenylene iodonium (DPI) and di-thienyl-iodonium (DTI) as inhibitors of NOX and other flavin dehydrogenases for the treatment and prevention of cancer and inflammation-related conditions. Several of these inhibitors displayed potency in vitro that were superior to their parent molecules and were effective against diverse cancer cell lines representing acute lymphocytic leukemia, chronic myelogenous leukemia, myeloma, large cell immunoblastic lymphoma, non-small cell lung cancer, colon, melanoma, and renal cancer. In vivo validation of DPI and DTI using human colon cancer xenografted mice yielded a statistically significant reduction in the average rate of tumor growth in mice administered either DPI or DTI compared to control mice.

Investigators at the NCI have synthesized a novel class of drugs capable of slowing ROS-mediated tumor growth by targeting NOX. The NCI seeks research co-development partners and/or licensees for further development of these novel iodonium analogs.

Potential Commercial Applications
  • Therapy to control chronic inflammatory conditions – including precancerous lesions
  • Targeted therapy for treating cancerous tumors expressing NOX
  • Diabetes
  • Neuropathies 
Competitive Advantages
  • Inactivate key kinases involved in tumor cell survival pathways
  • Optimized PDI specificity and selectivity lessens risk of off-target effects
  • Could become the first marketed drug, that depends on ROS to proliferate, to treat various cancers
Inventor(s)

James Halpern Doroshow M.D. (NCI), Prabhakar Risbood Ph.D., Jiamo Lu M.D., Krishnendu Roy Ph.D., Charles T Kane Jr. Ph.D., Md Tafazzal Hossain Ph.D.

Development Stage
Publications

Doroshow JH, et al. Antiproliferative mechanisms of action of the flavin dehydrogenase inhibitors diphenylene iodonium and di-2-thienyliodonium based on molecular profiling of the NCI-60 human tumor cell panel. [(PMID 22305747)]

Doroshow JH, et al. Effects of iodonium-class flavin dehydrogenase inhibitors on growth, reactive oxygen production, cell cycle progression, NADPH oxidase 1 levels, and gene expression in human colon cancer and xenografts.  [(PMID 23314043)]

Lu J, et al. Characterization of potent and selective iodonium-class inhibitors of NADPH oxidases. [(PMID 28709950)]

Patent Status
  • U.S. Patent Issued: U.S. Patent Number 10,131,659 , Issued 20 Nov 2018
  • U.S. Patent Issued: U.S. Patent Number 10,738,047 , Issued 11 Aug 2020
  • Foreign Filed: Europe - Patent Application 15717363.4 , Filed 06 Apr 2015
Therapeutic Area
Posted
Wednesday, April 14, 2021