Curcumin analogs with anti-tumor and anti-angiogenic properties
Patent Number: US7842705
Executive Summary:
General Description:
General toxicity and damage to normal cells and tissues is the main drawback of chemotherapy. This invention describes promising chemotherapeutic agents, based on the naturally occurring anti-angiogenic compound curcumin, that specifically target blood vessel growth in the tumor environment and are practically not toxic to normal vascular endothelial cells. The specificity of curcumin and its analogs action is based on targeting of Tissue Factor (TF) expression. TF is highly overexpressed in tumors and strongly stimulates expression of Vascular Endothelial Growth Factor (VEGF). Non-cancerous cells express very low amounts of TF and, therefore, are not targeted by the curcumin-like compounds. The inventors suggest a procedure for chemical synthesis of a variety of curcumin analogs and demonstrate that some of them are significantly more potent than curcumin in inhibiting TF, VEGF, and tumor cell proliferation.
Scientific Progress:
Future Directions:
Strengths:
Weaknesses:
Patent Status:
Publications PMIDs: 22532032, 18682687, 19854644, 22197802, 27128654
Publications:
Zhu S, Moore TW, Lin X, Morii N, Mancini A, Howard RB, Culver D, Arrendale RF, Reddy P, Evers TJ, Zhang H, Sica G, Chen ZG, Sun A, Fu H, Khuri FR, Shin DM, Snyder JP, Shoji M. Synthetic curcumin analog EF31 inhibits the growth of head and neck squamous cell carcinoma xenografts. Integr Biol (Camb). 2012
Jun;4(6):633-40. doi: 10.1039/c2ib20007d. Epub 2012 Apr 25. PubMed PMID:22532032; PubMed Central PMCID: PMC3734847.
Thomas SL, Zhong D, Zhou W, Malik S, Liotta D, Snyder JP, Hamel E, Giannakakou P. EF24, a novel curcumin analog, disrupts the microtubule cytoskeleton and inhibits HIF-1. Cell Cycle. 2008 Aug;7(15):2409-17. Epub 2008 Jun 9. PubMed PMID:18682687; PubMed Central PMCID: PMC2573855.
Sun A, Lu YJ, Hu H, Shoji M, Liotta DC, Snyder JP. Curcumin analog cytotoxicity against breast cancer cells: exploitation of a redox-dependent mechanism. Bioorg Med Chem Lett. 2009 Dec 1;19(23):6627-31. doi:10.1016/j.bmcl.2009.10.023. Epub 2009 Oct 8. PubMed PMID: 19854644; PubMed Central PMCID: PMC2791955.
Olivera A, Moore TW, Hu F, Brown AP, Sun A, Liotta DC, Snyder JP, Yoon Y, Shim H, Marcus AI, Miller AH, Pace TW. Inhibition of the NF-κB signaling pathway by the curcumin analog, 3,5-Bis(2-pyridinylmethylidene)-4-piperidone (EF31): anti-inflammatory and anti-cancer properties. Int Immunopharmacol. 2012 Feb;12(2):368-77. doi: 10.1016/j.intimp.2011.12.009. Epub 2011 Dec 22. PubMed PMID: 22197802; PubMed Central PMCID: PMC3372981.
Nagaraju GP, Zhu S, Ko JE, Ashritha N, Kandimalla R, Snyder JP, Shoji M, El-Rayes BF. Antiangiogenic effects of a novel synthetic curcumin analogue in pancreatic cancer. Cancer Lett. 2015 Feb 28;357(2):557-65. doi:10.1016/j.canlet.2014.12.007. Epub 2014 Dec 9. PubMed PMID: 25497868.
Rajitha B, Nagaraju GP, Shaib WL, Alese OB, Snyder JP, Shoji M, Pattnaik S, Alam A, El-Rayes BF. Novel synthetic curcumin analogs as potent antiangiogenic agents in colorectal cancer. Mol Carcinog. 2017 Jan;56(1):288-299. doi: 10.1002/mc.22492. Epub 2016 Apr 29. PubMed PMID: 27128654.
Inventor Bio: Shoji Mamoru
https://winshipcancer.emory.edu/bios/faculty/shoji-mamoru.html
Executive Summary:
- Invention Type: Therapeutic
- Patent Status: US Grant
- Patent Link: https://patents.google.com/patent/US7842705/
- Research Institute: Emory University
- Disease Focus: Cancer including metastatic cancer
- Basis of Invention: Chemical synthesis of curcumin analogs. Curcumin (diferuloylmethane) is the aromatic yellow pigment in curry, turmeric and mustard
- How it works: Curcumin analogs inhibit TF expression and VEGF expression in cancer cells and in vascular endothelial cells in the tumor microenvironment, thereby blocking tumor angiogenesis and growth
- Lead Challenge Inventor: James P. Snyder (deceased); Mamoru Shoji
- Inventors: James P. Snyder, Matthew C. Davis, Brian Adams, Mamoru Shoji, Dennis C. Liotta, Eva M. Ferstl, Ustun B. Sunay
- Development Stage: Pre-clinical, data from in vitro assays available
- Novelty:
- Curcumin analogs can be synthesized by reaction of commercially available aromatic aldehydes with ketones
- Curcumin analogs are more potent in TF and VEGF suppression and inhibition of cell growth than curcumin or the existing chemotherapeutic drugs (dacarbazine, thalidomide)
- Clinical Applications:
- Treatment of aggressive cancers, such as melanoma, glioblastoma
- Prevention of metastasis
General Description:
General toxicity and damage to normal cells and tissues is the main drawback of chemotherapy. This invention describes promising chemotherapeutic agents, based on the naturally occurring anti-angiogenic compound curcumin, that specifically target blood vessel growth in the tumor environment and are practically not toxic to normal vascular endothelial cells. The specificity of curcumin and its analogs action is based on targeting of Tissue Factor (TF) expression. TF is highly overexpressed in tumors and strongly stimulates expression of Vascular Endothelial Growth Factor (VEGF). Non-cancerous cells express very low amounts of TF and, therefore, are not targeted by the curcumin-like compounds. The inventors suggest a procedure for chemical synthesis of a variety of curcumin analogs and demonstrate that some of them are significantly more potent than curcumin in inhibiting TF, VEGF, and tumor cell proliferation.
Scientific Progress:
- Compounds EF24 and EF31 have been shown to have anti-cancer activity in mice in xenograft models of pancreatic, breast, and head and neck squamous cancers (see the publication list).
Future Directions:
- Clinical trials
Strengths:
- Promising anti-tumor and anti-metastatic agent with low toxicity
Weaknesses:
- Competition possible: Synthetic curcumin is now developed by Signpath Pharma.
Patent Status:
- Filing date: 2008-03-25
- Publication date: 2010-11-30
- Grant date: 2010-11-30
Publications PMIDs: 22532032, 18682687, 19854644, 22197802, 27128654
Publications:
Zhu S, Moore TW, Lin X, Morii N, Mancini A, Howard RB, Culver D, Arrendale RF, Reddy P, Evers TJ, Zhang H, Sica G, Chen ZG, Sun A, Fu H, Khuri FR, Shin DM, Snyder JP, Shoji M. Synthetic curcumin analog EF31 inhibits the growth of head and neck squamous cell carcinoma xenografts. Integr Biol (Camb). 2012
Jun;4(6):633-40. doi: 10.1039/c2ib20007d. Epub 2012 Apr 25. PubMed PMID:22532032; PubMed Central PMCID: PMC3734847.
Thomas SL, Zhong D, Zhou W, Malik S, Liotta D, Snyder JP, Hamel E, Giannakakou P. EF24, a novel curcumin analog, disrupts the microtubule cytoskeleton and inhibits HIF-1. Cell Cycle. 2008 Aug;7(15):2409-17. Epub 2008 Jun 9. PubMed PMID:18682687; PubMed Central PMCID: PMC2573855.
Sun A, Lu YJ, Hu H, Shoji M, Liotta DC, Snyder JP. Curcumin analog cytotoxicity against breast cancer cells: exploitation of a redox-dependent mechanism. Bioorg Med Chem Lett. 2009 Dec 1;19(23):6627-31. doi:10.1016/j.bmcl.2009.10.023. Epub 2009 Oct 8. PubMed PMID: 19854644; PubMed Central PMCID: PMC2791955.
Olivera A, Moore TW, Hu F, Brown AP, Sun A, Liotta DC, Snyder JP, Yoon Y, Shim H, Marcus AI, Miller AH, Pace TW. Inhibition of the NF-κB signaling pathway by the curcumin analog, 3,5-Bis(2-pyridinylmethylidene)-4-piperidone (EF31): anti-inflammatory and anti-cancer properties. Int Immunopharmacol. 2012 Feb;12(2):368-77. doi: 10.1016/j.intimp.2011.12.009. Epub 2011 Dec 22. PubMed PMID: 22197802; PubMed Central PMCID: PMC3372981.
Nagaraju GP, Zhu S, Ko JE, Ashritha N, Kandimalla R, Snyder JP, Shoji M, El-Rayes BF. Antiangiogenic effects of a novel synthetic curcumin analogue in pancreatic cancer. Cancer Lett. 2015 Feb 28;357(2):557-65. doi:10.1016/j.canlet.2014.12.007. Epub 2014 Dec 9. PubMed PMID: 25497868.
Rajitha B, Nagaraju GP, Shaib WL, Alese OB, Snyder JP, Shoji M, Pattnaik S, Alam A, El-Rayes BF. Novel synthetic curcumin analogs as potent antiangiogenic agents in colorectal cancer. Mol Carcinog. 2017 Jan;56(1):288-299. doi: 10.1002/mc.22492. Epub 2016 Apr 29. PubMed PMID: 27128654.
Inventor Bio: Shoji Mamoru
https://winshipcancer.emory.edu/bios/faculty/shoji-mamoru.html
