Manassantin compounds and methods of making and using the same
Adequate amount of oxygen (O2) is essential for human cells in order to fulfill their energy requirement. Hypoxia, or oxygen deprivation, is a prominent feature occurs within tumor cells due to decreased O2 delivery and increased O2 consumption. About 60% of solid tumors, including breast, prostate, colon, hepatocellular, pancreatic, brain, and ovarian cancers, have <1% O2 leading to hypoxia. To survive in hypoxic conditions, tumor cells have developed mechanisms to induce vascular growth, increase oxygen delivery, and promote cell survival. Tumor cells activate hypoxia-inducible transcription factor-1 (HIF-1) for orchestrating numerous cancer hallmarks that have crucial roles in tumor survival and progression under hypoxia. In addition, tumor cells with elevated HIF-1 are more resistant to traditional treatments such as radiation and chemotherapy. The importance of HIF-1 in tumor survival and progression made it a favorable target for cancer therapy. However, current HIF-1 inhibitors are not specific and have high toxicity.
Manassantin A and B are nature compounds that have been shown as potent inhibitors of HIF-1. Hong lab has worked out how to chemically synthesis manassantin compounds. As a result, manassantin no longer need to be extracted and can be produced in large quantity with high purity meeting therapeutic standards. Through various kinds of cellular assays, Hong lab demonstrated that their synthesized manassantin can effectively inhibit HIF-1. Manassantin inhibition of HIF-1 also successfully reduced the level of many other cancer hallmarks that are crucial in tumor survival and progression. Consistently, this invention can inhibit the growth of human cancer cell culture. Moreover, manassantin compounds demonstrated high potency (IC50<1µM) and low toxicity. This invention can be developed into a treatment for HIF-1 elevated tumors that is almost 60% of solid tumors. In addition, it can be used in combination with other traditional therapies to make cancerous tissues more accessible for treatments. The present invention also contains various forms of optimized manassatin compounds that can be developed into novel cancer therapeutics.
The present invention also provides a method of treating other hypoxia induced dysfunctions including:
- Heat disease
- Ocular neovascular disease
- Kidney disease
- Manassantin synthesis methods that can be readily adopted for industry production
- A variety of manassantin compounds ready to be used in therapeutic development
- High potency and low toxicity
- High reliability in tumor cell studies