Glucose transporter inhibitors
Patent Number: US9174951
Executive Summary:
General Description:
Cancer cells gain growth advantages in the microenvironment by shifting cellular metabolism from oxidative phosphorylation to glycolysis, the so-called Warburg effect. Targeting glycolysis by blocking glucose uptake represents a clinically relevant strategy for cancer treatment. To date, a number of small-molecule agents with the capability to suppress the activity or expression of glucose transporters have been reported. However, there remains a need for new glucose transporter inhibitors, particularly those exhibiting increased potencies.
The antitumor effect of ciglitazone, a PPAR agonist, was in part attributable to its ability to block glucose uptake. This lead optimization aimed to create a compound that targets exclusively the glucose uptake receptors, and not other pathways, led to compound 30 (5-(4-hydroxy-3-trifluoromethylbenzylidene)-3-[4,4,4-trifluoro-2-methyl-2-(2,2,2-trifluoro-ethyl)-butyl]-thiazolidine-2,4-dione) as the optimal agent. Compound 30 exhibited high potency in inducing apoptotic death in LNCaP prostate cancer cells through the suppression of glucose uptake (IC50, 2.5 μM). Equally important, thiazolidinedione compounds, including compound 30, displayed no cytotoxicity in the non-cancerous prostate and mammary epithelial cells.
Scientific Progress:
Glucose transporter inhibitor have been shown to overcome gemcitabine resistance in pancreatic cancer cells (ref. 4).
Future Directions:
Strengths:
Weaknesses:
Patent Status:
Publications:
1. S. Wei, H.-C. Chuang, W.-C. Tsai. H.-C. Yang. S.-R. Ho, A. J. Paterson, S. K. Kulp, and C.-S. Chen (2009) “Thiazolidinediones mimic glucose starvation in facilitating Sp1 degradation through the upregulation of b-TrCP’ Mol. Pharmacol. 76, 47-57
2. S. Wei, S. K. Kulp, C.-S. Chen (2010) Energy Restriction as an Antitumor Target for Thiazolidinediones. J. Biol. Chem. 285, 9780-9791
3. D. Wang, P.-C. Chu, C.N. Yang, R. Yan, Y.-C. Chung, S. K. Kulp, and C.-S. Chen (2012) “Development of a Novel Class of Glucose Transporter Inhibitors” J. Med. Chem. 55, 3827-3836
4. Lai IL, Chou CC, Lai PT, Fang CS, Shirley LA, Yan R, Mo X, Bloomston M, Kulp SK, Bekaii-Saab T, Chen CS. Targeting the Warburg effect with a novel glucose transporter inhibitor to overcome gemcitabine resistance in pancreatic cancer cells. Carcinogenesis. 2014 Oct;35(10):2203-13. doi: 10.1093/carcin/bgu124. Epub 2014 May 30. PubMed PMID: 24879635; PubMed Central PMCID: PMC4178465.
Inventor Bio: Ching-Shi Chen
http://www.pharmacy.ohio-state.edu/faculty-staff/users/chen844
Executive Summary:
- Invention Type: Therapeutic
- Patent Status: Active
- Patent Link: https://patents.google.com/patent/US9174951/
- Research Institute: Ohio State University
- Disease Focus: Cancer
- Basis of Invention: Tumor cells rely on glycolysis more heavily than non-cancerous cells. Inhibitors of glucose transport into the cell are, thereby, more toxic to cancer cells than to normal epithelial cells
- How it works: The compound synthesized by the inventors blocks the GLUT1 glucose transporter, limiting the glucose uptake and thus inhibiting glycolysis in cancer cells
- Lead Challenge Inventor: Ching-Shih Chen
- Inventors: Ching-Shih Chen, Dasheng Wang, Samuel K. Kulp
- Novelty:
- Highly potent glucose transporter inhibitor
- Highly potent glucose transporter inhibitor
- Clinical Applications:
- Prostate, breast, and pancreatic cancer treatment
- Prostate, breast, and pancreatic cancer treatment
General Description:
Cancer cells gain growth advantages in the microenvironment by shifting cellular metabolism from oxidative phosphorylation to glycolysis, the so-called Warburg effect. Targeting glycolysis by blocking glucose uptake represents a clinically relevant strategy for cancer treatment. To date, a number of small-molecule agents with the capability to suppress the activity or expression of glucose transporters have been reported. However, there remains a need for new glucose transporter inhibitors, particularly those exhibiting increased potencies.
The antitumor effect of ciglitazone, a PPAR agonist, was in part attributable to its ability to block glucose uptake. This lead optimization aimed to create a compound that targets exclusively the glucose uptake receptors, and not other pathways, led to compound 30 (5-(4-hydroxy-3-trifluoromethylbenzylidene)-3-[4,4,4-trifluoro-2-methyl-2-(2,2,2-trifluoro-ethyl)-butyl]-thiazolidine-2,4-dione) as the optimal agent. Compound 30 exhibited high potency in inducing apoptotic death in LNCaP prostate cancer cells through the suppression of glucose uptake (IC50, 2.5 μM). Equally important, thiazolidinedione compounds, including compound 30, displayed no cytotoxicity in the non-cancerous prostate and mammary epithelial cells.
Scientific Progress:
Glucose transporter inhibitor have been shown to overcome gemcitabine resistance in pancreatic cancer cells (ref. 4).
Future Directions:
- Pre-clinical animal studies
Strengths:
- Low toxicity of the compound for non-cancerous cells
Weaknesses:
- No in vivo validation of the compound effectiveness has been reported
Patent Status:
- Filing date: 2013-03-28
- Publication date and Grant date: 2015-11-03
Publications:
1. S. Wei, H.-C. Chuang, W.-C. Tsai. H.-C. Yang. S.-R. Ho, A. J. Paterson, S. K. Kulp, and C.-S. Chen (2009) “Thiazolidinediones mimic glucose starvation in facilitating Sp1 degradation through the upregulation of b-TrCP’ Mol. Pharmacol. 76, 47-57
2. S. Wei, S. K. Kulp, C.-S. Chen (2010) Energy Restriction as an Antitumor Target for Thiazolidinediones. J. Biol. Chem. 285, 9780-9791
3. D. Wang, P.-C. Chu, C.N. Yang, R. Yan, Y.-C. Chung, S. K. Kulp, and C.-S. Chen (2012) “Development of a Novel Class of Glucose Transporter Inhibitors” J. Med. Chem. 55, 3827-3836
4. Lai IL, Chou CC, Lai PT, Fang CS, Shirley LA, Yan R, Mo X, Bloomston M, Kulp SK, Bekaii-Saab T, Chen CS. Targeting the Warburg effect with a novel glucose transporter inhibitor to overcome gemcitabine resistance in pancreatic cancer cells. Carcinogenesis. 2014 Oct;35(10):2203-13. doi: 10.1093/carcin/bgu124. Epub 2014 May 30. PubMed PMID: 24879635; PubMed Central PMCID: PMC4178465.
Inventor Bio: Ching-Shi Chen
http://www.pharmacy.ohio-state.edu/faculty-staff/users/chen844
