Small molecule inhibitors for cancer treatment
The pivotal feature of deregulated energetic metabolism of cancer cells is posttranslational modification of 6-phosphofructo-1-kinase (PFK1), the key regulatory enzyme of glycolysis. Modified, highly active enzyme triggers deregulated glycolysis that produces abundant cytosolic NADH. In order, to maintain redox potential, redundant NADH must be re-oxidized by forming lactate while some NADH enters mitochondria and contributes to increased superoxide formation by OXPHOS. Superoxide/ROS generate mutations that at the early stages of cancer formation form onco-genes, while lactate contributes to immune escape, angiogenesis and metastases at invasive cancer stages.
Small-molecule inhibitors that dock to the ATP binding site of PFK1, were selected from the ZINC Drug NOW database by virtual screening using 3D-crystal structure of human PFK-P iso-enzyme as a model. Thirty-three compounds were selected and purchased for testing out of which, seven showed effective inhibition of PFK1 activities. As a result, deregulated glycolytic flux in cancer cells is brought under control and cytosolic NADH concentrations are reduced to those of the normal cells. In vitro tests on tumorigenic cell lines, isolated from different types of cancer, confirmed effective prevention of lactate and superoxide/ROS generation at low concentration of inhibitors. No cytostatic and cytotoxic effects of inhibitors were observed in tested cells, more-over the compounds were also virtually tested by Structure-activity relationship techniques. Reduced glycolytic fluxes were detected in treated tumorigenic cells by several analytical methods, confirming cancer specific modified PFK1s to be a target for inhibition.
- Partial inhibition of cancer specific PFK1 enzymes reduces glycolytic flux to that of the normal cells.
- Reduced glycolytic flux prevents lactate and superoxide/ROS generation.
- Identical small-molecule inhibitors can be used for prevention of lactate and superoxide/ROS generation.
- While reduction of superoxide/ROS generation prevents mutations at the early phases of cancer development, reduction of lactate formation is essential for treating the invasive cancers.
- No negative cytostatic and cytotoxic effects of inhibitors are detected.
- Inhibitors are effective at low concentrations when administered periodically.
- Low cost of compounds.
Fields of use: Biotechnology, Cancer treatmen
Technology Readiness Level: TRL3
Intellectual property: Patent pending
Partner sought: R&D collaboration to further develop the technology, licensing or sell of IP rights.
Next steps needed: Partner search to further development