ROS-Activated Compounds as Selective Anti-Cancer Therapeutics
Patent Number: US20130230542
Executive Summary:
General Description:
The currently available cancer chemotherapy treatments do not exhibit absolute specificity toward the tumor cells, so serious side effects of cancer treatments are common. This invention promotes targeting of cancer cells exploiting the special features of cancer cell metabolism. Some cancers, like acute myeloid leukemia (AML), use reactive oxygen species to endogenously activate cell proliferation and blood vessel growth. Thus, many cancers display increases in reactive oxygen species (ROS). This finding is translated into a therapeutic strategy by synthesis of organic compounds that release their cytotoxic component in response to the ROS exposure. The compounds described in the invention show high cytotoxicity toward several cancer cell lines and comparatively low cytotoxicity in non-cancerous cells.
Scientific Progress:
Cytotoxicity of ROS-activated RAC1 compound and one other formulation (compound 14) has been demonstrated to be is 8-9 times higher in AML cells than in normal lymphocytes (ref 1 and 2).
Future Directions:
Strengths:
Weaknesses:
Patent Status:
Publications:
1: Thowfeik FS, AbdulSalam SF, Wunderlich M, Wyder M, Greis KD, Kadekaro AL, Mulloy JC, Merino EJ. A ROS-Activatable Agent Elicits Homologous Recombination DNA Repair and Synergizes with Pathway Compounds. Chembiochem. 2015 Nov;16(17):2513-21. doi: 10.1002/cbic.201500304. Epub 2015 Nov 2. PubMed PMID:26419938; PubMed Central PMCID: PMC4758217.
2: Bell-Horwath TR, Vadukoot AK, Thowfeik FS, Li G, Wunderlich M, Mulloy JC, Merino EJ. Novel ROS-activated agents utilize a tethered amine to selectively target acute myeloid leukemia. Bioorg Med Chem Lett. 2013 May 15;23(10):2951-4. doi: 10.1016/j.bmcl.2013.03.048. Epub 2013 Mar 26. PubMed PMID: 23578690; PubMed Central PMCID: PMC3677216.
Inventor Bio: Edward J. Merino
http://www.artsci.uc.edu/departments/chemistry/faculty-and-staff/Directory.html?eid=merinoed
Executive Summary:
- Invention Type: Therapeutic
- Patent Status: Granted
- Patent Link: https://patents.google.com/patent/US20130230542/
- Research Institute: University of Cincinnati
- Disease Focus: Cancer
- Basis of Invention: Chemical synthesis of compounds that generate a potent electrophile in the presence of the reactive oxygen species (ROS). Thus, phenol is transferred to DNA to form a hydroxy-N2,3-benzetheno-2′-deoxyguanosine adduct, which is cytotoxic
- How it works: In a variety of cancers, tumor microenvironment is enriched in reactive oxygen species. The invented compounds are activated by ROS, increasing the specificity of cancer treatment
- Lead Challenge Inventor: Edward J. Merino
- Inventors: Edward J. Merino, James C. Mulloy, Guorui Li, Tiffany Bell-Horwath
- Development Stage: In vitro data in cancer cell lines
- Novelty:
- Increased specificity of therapy due to reagent activation by ROS abundant in tumor microenvironment
- Clinical Applications:
- Leukemia
- Renal cancer
- CNS cancers
- Leukemia
General Description:
The currently available cancer chemotherapy treatments do not exhibit absolute specificity toward the tumor cells, so serious side effects of cancer treatments are common. This invention promotes targeting of cancer cells exploiting the special features of cancer cell metabolism. Some cancers, like acute myeloid leukemia (AML), use reactive oxygen species to endogenously activate cell proliferation and blood vessel growth. Thus, many cancers display increases in reactive oxygen species (ROS). This finding is translated into a therapeutic strategy by synthesis of organic compounds that release their cytotoxic component in response to the ROS exposure. The compounds described in the invention show high cytotoxicity toward several cancer cell lines and comparatively low cytotoxicity in non-cancerous cells.
Scientific Progress:
Cytotoxicity of ROS-activated RAC1 compound and one other formulation (compound 14) has been demonstrated to be is 8-9 times higher in AML cells than in normal lymphocytes (ref 1 and 2).
Future Directions:
- Pre-clinical studies on animal model
Strengths:
- High reagent selectivity in killing cancer cells
Weaknesses:
- Lack of animal data
Patent Status:
- Filing Date: 2013-03-01
- Publication date: 2013-09-05
- Other version: US9394233B2 (Grant)
Publications:
1: Thowfeik FS, AbdulSalam SF, Wunderlich M, Wyder M, Greis KD, Kadekaro AL, Mulloy JC, Merino EJ. A ROS-Activatable Agent Elicits Homologous Recombination DNA Repair and Synergizes with Pathway Compounds. Chembiochem. 2015 Nov;16(17):2513-21. doi: 10.1002/cbic.201500304. Epub 2015 Nov 2. PubMed PMID:26419938; PubMed Central PMCID: PMC4758217.
2: Bell-Horwath TR, Vadukoot AK, Thowfeik FS, Li G, Wunderlich M, Mulloy JC, Merino EJ. Novel ROS-activated agents utilize a tethered amine to selectively target acute myeloid leukemia. Bioorg Med Chem Lett. 2013 May 15;23(10):2951-4. doi: 10.1016/j.bmcl.2013.03.048. Epub 2013 Mar 26. PubMed PMID: 23578690; PubMed Central PMCID: PMC3677216.
Inventor Bio: Edward J. Merino
http://www.artsci.uc.edu/departments/chemistry/faculty-and-staff/Directory.html?eid=merinoed
