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It is estimated that 90% of the lung cancer are caused by cigarette smoking and lung cancer remains the leading cause of cancer-related deaths in the USA with a less than 5% overall survival rate. Smoking tobacco products is the major factor that contributes to the lung cancer. It is known that there are two major lung cancers, small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). Unfortunately there is no successful or very efficient therapeutic strategy so far. SCLC grows rapidly and metastasizes early, and patient usually dies within 1-2 years since there is basically no efficient treatment for them. Recently, it has been discovered that unlike normal lung tissues, upregulation of telomerase, an enzyme that restores the length of the telomere, occurs in 98% of SCLC. As for NSCLC, telomerase activity is regarded as an important prognostic factor for NSCLC patients after surgical resection. Such discoveries suggest that the telomerase expression is an adverse prognostic factor for both lung cancers. Telomerase, an enzyme that maintains the ends of chromosomes (telomeres), is activated in the vast majority of lung cancers, but telomerase remains dormant in most normal tissues. Thus, telomerase is an attractive target for therapy of lung. Because telomerase activity is absent from most normal tissue, and inhibitors of telomerase are NOT cytotoxic, treatment of breast cancer patients with a telomerase inhibitor would not afford the detrimental biological effects usually associated with most chemotherapy treatments.
There are several known mechanisms, which therapeutic agents can use to inhibit telomerase. For example, Geron has pioneered the development of two oligonucleotides (GRN163 and GRN163L) that are antagonists of the RNA component of the telomerase enzyme. However, these large insoluble compounds are difficult to deliver in effective and safe concentrations. There are very few small molecules known to inhibit telomerase. There appear to work by different mechanisms, which are not fully understood. Among these, rubromycin is the most potent. It is reported to inhibit telomerase at concentration of less than 2.0 micromolar and to kill cancer cells in vitro. Because it is a cytostatic agent rather than a cytotoxic agent, potential side effects would be low in comparison with other anticancer agents. Therefore, rubromycin and its analogs are anticipated to be useful as a future non-toxic method of chemotherapy.
The inhibitory activity of rubromycin has been proposed to reside in a key part of its structure, the so-called pharmacophore. The designated portion of the molecule is called a 5, 6-aryloxyspiroketal and it is a highly unusual arrangement of atom that has proven difficult to build. However, the synthetic strategy that I have developed enables one to easily build this structure. Nobody else possesses this synthetic ability. Therefore, I am able to build an assortment of 5,6-aryloxyspiroketals, so that I might determine which other part of its total structure are responsible for telomerase inhibition. In addition, I could optimize both inhibitory potency and selectivity. This mechanism of inhibition is currently unknown.
1) Synthesize an assortment of compounds based on the rubromycin backbone. 2) Screen these libraries for telomerase inhibition in order to identify the pharmacophore and optimize both potency and selectivity. 3) Provide access to materials such as overproducing cell lines and expertise in the in vitro and cell-based screening of telomerase inhibition.
The convergent synthesis of the key phamacophore is highly innovative. There are only a few small molecule inhibitors known for telomerase. While telomerase and its inhibitors are being studied in academic and industrial settings, because of the complexity and scarcity of rubromycin and it is not likely this compound or derivatives are being investigated by others. However, it is most potent inhibitor and because of its complexity its scaffold would likely afford an inhibitor with the greatest selectivity among small molecule inhibitors as a potential lung cancer treatment. |
